Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof

ABSTRACT

The present invention disclosed a class of pyrimidine or pyridine compounds, pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof, preparation method therefor and pharmaceutical compositions and pharmaceutical uses thereof. The compounds can inhibit the variants of EGFR (Epidermis Growth Factor Receptor) proteinases, and therefore can inhibit the growth of a variety of tumor cells effectively. The compounds can be used to prepare antitumor drugs, used for the treatment, combined therapy or prevention of various different cancers. The compounds can overcome the drug resistance induced by the existing first-generation EGFR inhibitors such as gefitinib, erlotinib and so on. Particularly, the compounds can be used to prepare drugs for treating or preventing diseases, disturbances, disorders or conditions mediated by epidermis growth factor receptor variants (such as L858R activated mutants, Exon19 deletion activated mutants and T790M resistant mutants).

FIELD OF THE INVENTION

The present invention pertains to the field of pharmaceutical chemistry,and particularly, to pyrimidine or pyridine compounds andpharmaceutically acceptable salts, stereoisomers, prodrugs and solvatesthereof; a method for preparing the same; a pharmaceutical compositioncontaining the same and pharmaceutical use of the same. In particular,the present invention relates to pyrimidine or pyridine compounds andpharmaceutically acceptable salts, stereoisomers, prodrugs and solvatesthereof; a method for preparing the same; a pharmaceutical compositioncontaining the compounds, pharmaceutically acceptable salts,stereoisomers, prodrugs and/or solvates thereof, particularly usefulpolymorphs of the compounds and salts thereof, and a use of thecompounds and pharmaceutically acceptable salts, stereoisomers, prodrugsand solvates thereof in the preparation of a medicament for treatingdiseases mediated by various EGFR forms (e.g. activated mutants and/orresistant mutants).

BACKGROUND

Cancer is becoming the deadliest “killer” to human beings. In recentyears, the total number of people died for cancer is close to 2 millioneach year in China. Although a variety of discovery of treatmentpathways and drugs have brought hope for cancer patients, theseconventional treatments still have many drawbacks, such as large sideeffect, poor treatment effect, tumor recurrence, metastasis and so on.There is an urgent need for new treatment techniques to improve the lowsuccess rate of cancer treatment. The recent emergence of individualizedchemotherapy and targeted therapy has brought new hope to lung cancertreatment. Tumor molecular targeted therapy is a treatment method inwhich the key molecules that closely relate to the tumor growth willselectively kill the tumor cells through chemical or biological means.Targeted therapy has many characteristics, such as high specificity,high selectivity and mild side effects. When targeted therapy is used incombination with traditional chemotherapy, radiotherapy or tumorimmunization, the efficacy can be greatly enhanced and the postoperativerecurrence can be reduced. Tumor targeted therapy has rapidly develop inrecent years, and becomes the emerging field of cancer treatment andfuture development trend.

Protein tyrosine kinases (PTKs) are a class of protein enzymes that cancatalyze the phenolic hydroxyl phosphorylation on tyrosine residue of avariety of important proteins, thereby activating the biologicalactivity of functional proteins. This reaction process plays a veryimportant role in the intracellular signal transduction pathway, for itregulates a series of physiological and chemical processes such as cellgrowth, differentiation and death. Protein tyrosine kinase dysfunctioncan cause a series of diseases in the body. There are many studiesshowing that the activation of more than half of the original cancergene and oncogene are associated with protein tyrosine kinase, andprotein tyrosine kinase abnormal expression can lead to disorders ofcell proliferation regulation, thereby leading to tumor genesis. Inaddition, tyrosine kinase abnormal expression is also closely associatedwith tumor invasion and metastasis, tumor neovascularization, tumorresistance to chemotherapy. Tyrosine kinase has become a very importanttarget for the development of antitumor drugs.

Epidermal growth factor receptor (EGFR) is a receptor tyrosine proteinkinase, and a transmembrane protein in the ErbB receptor family.

EGFR regulates proliferation, survival, adhesion, migration anddifferentiation of cells, which is hyperactivated or sustained in avariety of tumor cells, such as lung cancer cells, breast cancer cells,prostate cancer cells and the like. Abnormal activation of EGFR plays akey role in tumor transformation and growth. Blocking activation of EGFRhas been clinically proven as one of the effective targeted therapymethods for tumor cell. EGFR was expressed in 50% of NSCLC (non-smallcell lung cancer) cases, which makes EGFR and family members thereof amajor candidate for targeted therapy. Gefitinib and erlotinib are thefirst generation of small molecule inhibitors of EGFR, and primarilyused as drugs for treating advanced NSCLC. Clinical results show thatgefitinib or erlotinib has effect on about 10% of white NSCLC and about35% of Asian NSCLC patients. The analysis shows that the response rateto EGFR-tyrosine kinase inhibitor (TI) in most NSCLC patients with EGFRactivation mutations was significantly higher than that in EGFR wildtype of NSCLC patients.

However, clinical studies have shown that many patients soon (12-14months) have been resistant to these small molecule inhibitors of EGFR,ie, acquired drug resistance. Gatekeeper residue of T790M mutation is amutation point in EGFR 20 exon and is one of the major mechanismsleading to drug resistance. Studies on a new generation of inhibitor forthese EGFR mutations have recently been very successful. Afatinib is apotent and irreversible double inhibitor of EGFR and human epidermalgrowth factor receptor 2 (HER2) tyrosine kinases. Other similarmulti-target, highly active and irreversible inhibitors, such ascanertinib, and dacomitibib are also in later clinical trials. Thesenovel second-generation irreversible inhibitors have a strong inhibitoryeffect on EGFR with L858R and T790M mutants, and have a significanteffect on gefitinib or erlotinib-resistant cancer patients. However,these second-generation EGFR mutant inhibitors also have a stronginhibitory effect on wild-type EGFR (WT-EGFR). Clinical studies haveshown that the inhibition of wild-type EGFR can lead to drug toxicityand side effects in most patients, such as rash or diarrhea in the humanbody.

In order to overcome the toxicity and side effects of thesecond-generation EGFR inhibitors, it is necessary to reduce theinhibitory effect on wild-type EGFR (WT-EGFR). A new generation (i.e.the third generation) of EGFR inhibitors should remain a stronginhibition against EGFR L858R activated mutants, Exon19 deletionactivated mutants and T790M resistant mutants, and show a relatively lowinhibitory effect on WT-EGFR and other tyrosine protein kinasereceptors. Such compounds can be used not only in the treatment ofcancer patients with a resistance to EGFR L858R-activated mutants andExon19 deletion-activated mutants, but also in the treatment of cancerpatients with EGFR-T790M resistant mutants resulting to the resistanceagainst the first-generation EGFR inhibitors such as gefitinib,erlotinib or icotinib. The third-generation EGFR inhibitor, AZD9291, hasa beneficial clinical effect, but its major metabolite, AZ5104, has astrong inhibitory effect on wild-type EGFR (WT-EGFR), which is the mostprobable incentive inducing the most common side effects such as aclinically common rash, diarrhea and the like.

The present invention shows many pyrimidine or pyridine compounds thathave a high inhibitory activity against EGFR mutant(s), but onlyrelatively low inhibitory effects on wild-type EGFR. The compounds ofthe present invention have good physicochemical properties and safetytoxicity parameters. Such compounds will have a better effect in thetreatment of cancer with EGFR-activated mutants and/or EGFR-resistantmutations.

The present invention relates to certain pyrimidine or pyridinecompounds and pharmaceutically acceptable salt thereof, and can be usedfor the treatment or prevention of the disease or condition mediated bysome mutated forms of epidermal growth factor receptors (e.g., L858Ractivated mutants, Exon19 deletion activated mutants, and T790Mresistant mutants). Such compounds and pharmaceutically acceptablesalts, stereoisomers, prodrugs and solvates thereof can be used for thetreatment or prevention of many different cancers. The present inventionalso relates to a pharmaceutical composition comprising the compound anda pharmaceutically acceptable salt, stereoisomer, prodrug and solvatethereof, in particular, the useful polymorphs of the compound and salt;the useful intermediates used for preparing the said compounds; and themethod for the treating diseases mediated by EGFR in the form ofactivated and/or resistant mutants by the compounds, pharmaceuticallyacceptable salts, stereoisomers, prodrugs and solvates thereof.

Therefore, there is an urgent need for a new type of compound,especially a compound with novel skeleton, to solve problems such aspoor resistance, poor selectivity and the like. In the following list ofdocuments, the patent or non-patent documents (journals, magazines,manuals and books, etc.) that are closest to patent applications arecited:

-   1. New England Journal of medicine, 2008, vol. 358, pp. 1160-1174;-   2. Chemical and Biophysical Research Communications, 2004, vol. 319,    pp. 1-11;-   3. Science, 2004, vol. 304, pp. 1497-1500;-   4. New England Journal of medicine, 2004, vol. 350, pp. 2129-2139;-   5. Molecular Cancer Therapeutics, 2014, vol. 13, pp. 1468-1479;-   6. Journal of Medicinal Chemistry, 2014, vol. 57, pp. 8249-8267;-   7. WO2013014448A1, corresponding to CN103702990A;-   8. WO2013108754A1;-   9. CN103374000A;-   10. CN103804303A;-   11. WO2013184766A1; and-   12. WO2009051822A1.

It should be stated that the above-mentioned patent or non-patentdocuments is only representative documents and are not a complete listof all the relevant literature. The entire disclosure of theabove-mentioned patent or non-patent document is hereby incorporated inits entirety for a reference, and in the cases where there is aconflict, the description in the present application document shallprevail.

The current EGFR-TKI does still not solve the clinical problems causedby drug resistance, and the most of existing drugs are EGFR reversibleor irreversible inhibitors based on quinazoline or quinolinamine as thebasic nucleus, and they are still inevitably brought to the side effectsof poor selectivity to EGFR wild-type cells. Therefore, there is anurgent need for a new type of compounds, especially compounds with novelskeletons, so as to solve problems such as poor drug resistance andselectivity.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a pyrimidine orpyridine compound represented by the following formula (I) and apharmaceutically acceptable salt, stereoisomer, prodrug molecule orsolvate thereof. The compounds can inhibit the variants of epidermalgrowth factor receptor (EGFR) protein kinases, and therefore can inhibitthe growth of a variety of tumor cells effectively. The compounds can beused to prepare antitumor drugs, used for the treatment or prevention ofvarious different cancers. The compounds can overcome the drugresistance induced by the existing Gefitinib, erlotinib and so on. Moreparticularly, the compounds can be used to prepare drugs for treating orpreventing diseases, disturbances, disorders or conditions mediated byEGFR variants (such as L858R activated mutants, Exon19 deletionactivated mutants and/or T790M resistant mutants).

It is another object of the present invention to provide a method forpreparing the above-mentioned compounds.

It is a further object of the present invention to provide apharmaceutical composition comprising one or more selected from thegroup consisting of the pyrimidine or pyridine compounds,pharmaceutically acceptable salt, stereoisomer, prodrug molecule andsolvate thereof, and one or more pharmaceutical excipients.

It is a further object of the present invention to provide a use of theabove-mentioned pyrimidine or pyridine compounds, pharmaceuticallyacceptable salt, stereoisomer, prodrug molecule and/or solvates thereof,and the above pharmaceutical composition in preparing a dug for treatingor preventing diseases, disturbances, disorders or conditions mediatedby a variant EGFR, particularly in preparing a drug for treating orpreventing one or more cancers.

It is a further object of the present invention to provide a method oftreating or preventing a disease, disorder, disorder or conditionmediated by a variant EGFR, in particular one or more cancers.

It is a further object of the present invention to provide a combinedtreatment of cancer, that is to say, a method for treating cancer byusing one or more of selected from the above pyrimidine or pyridinecompounds, pharmaceutically acceptable salt, stereoisomer, prodrugmolecule and solvates thereof, or the pharmaceutical compositionaccording to the present invention in combination with conventionalsurgery, radiotherapy, chemotherapy or tumor immunotherapy.

It is the first aspect of the invention to provide a compound of formula(I) or a pharmaceutically acceptable salt, stereoisomer, prodrugmolecule or solvate thereof:

wherein,

R¹ is hydrogen, deuterium, halogen or cyano;

R² is a C1-C6 alkyl, CD₃, or halogen-substituted C1-C6 alkyl;

X is NR³ or O;

Y is NHC(═O) or NHS(═O)₂, and the nitrogen in said NHC(═O) or NHS(═O)₂is bonded to the benzene ring in formula (I);

R³ is a C1-C6 alkyl, C1-C6 alkoxy, CD₃, C1-C6 alkoxy C1-C6 alkyl;

R⁴ is a C1-C3 alkyl, unsubstituted or substituted with 1-3 substituents,wherein said substituent is a C1-C3 alkyl, CD₃, C1-C3 alkoxy,methanesulfonyl, NR⁷R⁸ or a 3- to 6-membered heterocyclic groupcontaining 1 to 2 heteroatoms selected from N and O, unsubstituted orsubstituted with hydroxy or C1-C3 alkyl;

or, R³ and R⁴, together with the nitrogen atom to which they are bonded,form a 4-6 membered heterocyclic ring containing 1 to 4 nitrogen oroxygen and having one or more substituents, and the substituent isamino, dimethylamino, C1-C3 alkoxy, or a 4- to 6-membered heterocyclicgroup containing 1 to 2 heteroatoms selected from N and O, unsubstitutedor substituted with C1-C3 alkyl;

R⁵ is a fused ring formed by two rings, and the fused ring formed by tworings is optionally substituted with 1-3 substituents, wherein the tworings forming the fused ring are each independently benzene, a5-7-membered heterocyclic ring or a 5-7-membered heteroaromatic ring,wherein the 5-7 membered heterocyclic or 5-7 membered heteroaromaticring contains 1-4 heteroatoms selected from S, N or O, and thesubstituent is oxo group (═O) or R⁶,

R⁶ is hydrogen, C1-C3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl),CD₃, C1-C3 alkylsulfonyl, C3-C6 cycloalkyl (e.g., C3-C4 cycloalkyl), 4-6membered heterocyclyl, 4-6 membered heteroaryl, or halogen-substitutedC1-C3 alkyl (e.g., a fluorine-substituted C2-C3 alkyl), wherein the 4-6membered heterocyclyl or 4-6 membered heteroaryl contains 1 to 3heteroatoms selected from N, O and S and is optionally substituted withC1-C2 alkyl;

R⁷ and R⁸ are each independently C1-C3 alkyl, CD₃, C1-C3 alkoxy or C3-C5cycloalkyl;

and when R¹ is hydrogen, R² is methyl, X is NCH₃, Y is NHC(═O), R⁴ isdimethylaminoethyl, R⁵ cannot be

when R¹ is hydrogen, R² is methyl, X is NR₃, Y is NHC(═O), R³ is methyl,R⁴ is dimethylaminoethyl, R⁵ is

R⁶ is methyl, no hydrogen in any one of R¹, R², R³, R⁴ and R⁶ can besubstituted by deuterium.

In one preferred embodiment of the present application,

R¹ is hydrogen, deuterium, fluorine, chlorine or cyano;

R² is a C1-C3 alkyl, CD₃, or C1-C3 alkyl substituted with 1 to 3fluorines or chlorines;

X is NR³ or O;

R³ is a C1-C3 alkyl, CD₃, or C1-C3 alkoxyC1-C3alkyl;

Y is NHC(═O) or NH S(═O)₂;

R⁴ is selected from the following groups:

Or, when X is NR³, R³ and R⁴, together with the nitrogen atom to whichthey are bonded, form a nitrogen-containing heterocyclic ring withsubstituent(s), and the nitrogen-containing heterocyclic ring withsubstituent(s) is selected from the following heterocyclic groups

R⁵ is a group selected from the following groups:

R⁶ is hydrogen, methyl, CD₃, ethyl, isopropyl, methylsulfonyl, C3-C6cycloalkyl (e.g., C3-C4 cycloalkyl, cyclopropyl), orfluorine-substituted C1-C3 alkyl (e.g., 2,2-difluoroethyl,2,2,2-trifluoroethyl); preferably, R⁶ is selected from hydrogen, methyl,CD₃, ethyl or methylsulfonyl;

and when R¹ is hydrogen, R² is methyl, X is NCH₃, Y is NHC(═O), R⁴ isdimethylaminoethyl, R⁵ cannot be

when R¹ is hydrogen, R² is methyl, X is NR₃, Y is NHC(═O), R³ is methyl,R⁴ is dimethylaminoethyl, R⁵ is

R⁶ is methyl, no hydrogen in any one of the groups of R¹, R², R³, R⁴, R⁶can be substituted by deuterium.

In another preferred embodiment of the present application, R¹ ishydrogen, R² is methyl or CD₃, X is NR³, R³ is CH₃, CD₃, ethyl ormethoxyethyl, Y is NHC(═O) or NHS(═O)₂, R⁴ is dimethylaminoethyl, R⁵ isselected from the following groups:

wherein, R⁶ is hydrogen, methyl, CD₃, ethyl, isopropyl, methylsulfonyl,C3-C6 cycloalkyl (e.g., C3-C4 cycloalkyl, cyclopropyl), orfluorine-substituted C1-C3 alkyl (e.g., 2,2-difluoroethyl,2,2,2-trifluoroethyl); preferably, R⁶ is hydrogen, methyl, CD₃, ethyl,or methylsulfonyl;

In another preferred embodiment of the present application, R¹ ishydrogen, R² is methyl or CD₃, X is NR³, R³ is CH₃, CD₃, ethyl ormethoxyethyl, Y is NHC(═O) or NHS(═O)₂, R⁴ is dimethylaminoethyl, R⁵ isselected from the following groups:

In another preferred embodiment of the present application, R¹ ishydrogen; R² is a methyl or CD₃, X is NR³, R³ is CD₃ or ethyl; Y isNHC(O) or NHS(═O)₂; R⁴ is selected from the following groups:

R⁵ is a group selected from the following groups:

wherein R⁶ is hydrogen, methyl, CD₃, ethyl, isopropyl, methylsulfonyl,C3-C6 cycloalkyl (e.g., C3-C4 cycloalkyl, cyclopropyl), orfluorine-substituted C1-C3 alkyl (e.g., 2,2-difluoroethyl,2,2,2-trifluoroethyl); preferably, R⁶ is hydrogen, methyl, CD₃, ethyl,or methylsulfonyl.

In another preferred embodiment of the present application, R¹ ishydrogen; R² is a methyl or CD₃, X is NR³, R³ is CD₃ or ethyl; Y isNHC(═O) or NHS(═O)₂; R⁴ is selected from the following groups:

R⁵ is a group selected from the following groups:

In another preferred embodiment of the present application, R¹ ishydrogen; R² is a methyl, X is NCH₃; Y is NHC(═O) or NHS(═O)₂; R⁴ isdimethylaminoethyl, R⁵ is a group selected from the following groups:

In a most preferred embodiment of the present application, the compoundof formula (I) is selected from:

The second aspect of the present application provides a method forpreparing compounds represented by the above formula (I) or apharmaceutically acceptable salt thereof, for example, using a methodrepresented by the following general reaction processes, in which thereaction sequences of certain two-step or multi-step reactions can beexchanged and do not necessarily have to be exactly the same as thesequences shown in the following reaction processes. Compounds A1, A2,A4, D1, R³R⁴NH, R⁴OH, R⁵H and R⁵Z in the following general reactionprocesses may be commercially available or may be prepared from othercommercially available compounds according to methods known in the art.The preparation method is described in detail in the examples.

wherein R¹, R², R³, R⁴ and R⁶ are defined and preferred as describedabove,

In the above general reaction process, 2,4-dichloropyrimidine compoundA1 reacts with indole compound A2 in the presence of ferric chloride toproduce compound A3. In the presence of p-toluenesulfonic acid, compoundA3 and compound A4 react to form compound A5. The fluorine atom incompound A5 is substituted with a secondary amine R³R⁴NH in the presenceof potassium carbonate to give product A6. Nitrobenzene is convertedinto aniline compound A7 through a catalytic hydrogenation or areduction reaction by iron powder. After reacting with acryloyl chlorideA8, aniline is converted into the final product A9. Upon addition of anacid, product A9 can be converted into different salts, for example,methanesulfonate salt A10 can be obtained by treating withmethanesulfonic acid, and hydrochloric acid salt A11 can be obtained bytreating with hydrochloric acid. In these salts, the ratio of acid tocompound A9 varies in different molecules. A compound A9 can react with1-4 mole equivalent of acid molecules to form a salt, mostly, diacid ortriacid salt.

wherein, R¹, R², R⁴ and R⁶ are defined and preferred as described above,

In the above general reaction sequence, the fluorine atom in compound A5is substituted with alcohol R⁴OH in the presence of sodium hydride togive the product B1. Nitrobenzene is converted into aniline compound B2through a catalytic hydrogenation or reduction reaction by iron powder.After reacting with acryloyl chloride A8, aniline is converted into thefinal product B3. Upon addition of an acid, the product B3 can beconverted into different salts, for example, methanesulfonate salt B4can be obtained by treating with methanesulfonic acid, and hydrochloricacid salt B5 can be obtained by treating with hydrochloric acid. Inthese salts, the ratio of acid to compound B3 varies in differentmolecules. A compound B3 can react with 1-4 mole equivalent of acidmolecules to form a salt, mostly, diacid or triacid salt.

wherein, R¹, R², R³, R⁴ and R⁶ are defined and preferred as describedabove,

In the above general reaction sequence, after reacting with vinylsulfonyl chloride C1, aniline A7 is converted into the final product C2.Upon addition of acid, the product C2 can be converted into differentsalts, for example, methanesulfonate salt C3 can be obtained by treatingwith methanesulfonic acid, and hydrochloric acid salt C4 can be obtainedby treating with hydrochloric acid. In these salts, the ratio of acid tocompound C2 varies in different molecules. A compound C2 can react with1-4 mole equivalent of acid molecules to form a salt, mostly, diacid ortriacid salt.

wherein, R¹, R², R³, R⁴ and R⁶ are defined and preferred as describedabove, wherein Z is a borate, a tin or zinc substituent,

In the above general reaction sequence, the 2,4-dichloropyrimidinecompound A1 is subjected to a substitution reaction with thetwo-membered fused ring compound R⁵H under suitable known conditions oris subjected to a catalytic coupling reaction with the compound R⁵Z toproduce the compound D2. Alternatively, the amine group of compound D1may be reacted with a suitable reagent and then under suitableconditions to form a two-member fused ring substituent R⁵ in D2. In thepresence of p-toluenesulfonic acid, compound D2 and compound A4 react toform compound D3. The fluorine atom in D3 is substituted with thesecondary amine R³R⁴NH in the presence of potassium carbonate to giveproduct D4. Nitrobenzene is converted into aniline D5 through acatalytic hydrogenation or reduction reaction by iron powder. Afterreacting with acryloyl chloride A8, aniline gave the final product D6.After treating with an acid, product D6 can be converted into differentsalts, for example, methanesulfonate salt D7 can be obtained by treatingwith methanesulfonic acid, and hydrochloric acid salt D8 can be obtainedby treating with hydrochloric acid. In these salts, the ratio of acid tocompound D6 varies in different molecules. A compound D6 can react with1-4 mole equivalent of acid molecules to form a salt, mostly, diacid ortriacid salt.

wherein, R¹, R², R⁴, R⁵ and X are defined and preferred as describedabove,

In the above general reaction sequence, aniline intermediate compound E1(A7, B2, D5) may be reacted with acrylic anhydride E2 to form acrylamidecompound E3 (A9, B3, D6).

The third aspect of the present application provides a pharmaceuticalcomposition comprising a therapeutically effective amount of one or moreof compounds of formula (I), pharmaceutically acceptable salt thereof,stereoisomer, prodrug molecule and/or solvate thereof, and one or morepharmaceutical excipients. The above pharmaceutical composition is amedicament for the treatment or prevention of diseases, disturbances,disorders or conditions mediated by the EGFR in the form of activatedmutant or resistant mutant, in particular, for the treatment orprevention of one or more cancers.

The above-mentioned medicaments, according to the objective of thetreatment, may be in a variety of pharmaceutical forms, generallyincluding: tablets, pills, capsules, granules, suspensions, solutions,creams, ointments, powders, suppositories, aerosols, injections etc.

The fourth aspect of the present application provides a use of acompound of formula (I), a pharmaceutically acceptable salt, astereoisomer, a prodrug molecule and/or a solvate thereof in thepreparation of a medicament for treating or preventing a disorder ordisease mediated by EGFR in the form of activated mutant or resistantmutant. The disorder or disease includes, but is not limited to, ovariancancer, cervical cancer, colorectal cancer (e.g., colon adenocarcinoma),breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma,prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastriccancer, lung cancer (e.g., non-small cell lung cancer), hepatocellularcarcinoma, gastrointestinal stromal tumors (GIST), thyroid cancer,cholangiocarcinoma, endometrial cancer, renal carcinoma, anaplasticlarge cell lymphoma, acute myeloid leukemia (AML), multiple myeloma ormesothelioma.

In the present invention, the EGFR in the form of activated mutant orresistant mutant may be, for example, a L858R activated mutant, anExon19 deletion activated mutant and/or a T790M resistant mutant. Thus,the disease, disturbance, disorder or condition mediated by EGFR in theform of activated mutant or resistant mutant can be, for example, thedisease, disturbance, disorder or condition mediated by L85SR activatedmutant, Exon19 deletion activated mutant and/or T790M resistant mutant.

The compounds of formula (I), pharmaceutically acceptable salt,stereoisomer, prodrug molecule and solvate thereof according to theinvention, or pharmaceutical composition according to the invention canbe particularly used for treating or preventing disease, disturbance,disorder or condition mediated by EGFR in the form of activated mutantor resistant mutant, such as a disease, disturbance, disorder orcondition mediated by L858R activated mutant, Exon19 deletion activatedmutant and/or T790M resistant mutant, and may be used, for example, forpreventing or treating a cancer patient who has been resistant togefitinib, erlotinib, or icotinib.

In a further aspect of the present invention, there is provided a methodof combination therapy for treating cancer, comprising administering toa subject in need of treatment a therapeutically effective amount of oneor more pyrimidine or pyridine compounds of formula (I),pharmaceutically acceptable salts, stereoisomers, prodrug molecules andsolvates thereof, according to the invention, or a therapeuticallyeffective amount of a pharmaceutical composition according to theinvention, in combination with conventional surgical therapy,radiotherapy, chemotherapy or antitumor immunotherapy.

The compounds according to the present invention may be administrated inparallel, concurrently, sequentially, or separately with thechemotherapy or antitumor immunotherapy. The chemotherapy orimmunotherapy includes, but is not limited to, one or more of thefollowing types of antitumor agents: alkylating agent (e.g.,carboplatin, oxaliplatin, cisplatin, cyclophosphamide, nitrosourea,nitrogen mustard, melphalan), antimetabolite (e.g. gemcitabine), andanti-folic acid agent (e.g., 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytarabine, hydroxyurea), topoisomerase inhibitor (e.g.,etoposide, topotecan, camptothecin), anti-mitotic agent (e.g.,vincristine, vinblastine, vinorelbine, paclitaxel, taxotere), anti-tumorantibiotic (e.g., doxorubicin, bleomycin, doxorubicin, daunomycin,mitomycin C, actinomycin), antiestrogen drug (e.g., tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene), anti-androgen drug(e.g., bicalutamide, flutamide, nilutamide), LHRH antagonist or LHRHagonist (e.g., goserelin, leuprolide, and buserelin), aromataseinhibitor (e.g., anastrozole, letrozole), CYP17 cleavage enzymeinhibitor (such as abiraterone), anti erbB2 antibody trastuzumab[Herceptin], anti-EGFR antibody cetuximab [Erbitux]; inhibitor oftyrosine kinase, serine/threonine kinases (e.g., imatinib, nilotinib,sorafenib, trametinib, crizotinib); cyclin-dependent kinase inhibitor(e.g., CDK4 inhibitor, palbociclib), anti-human vascular endothelialgrowth factor antibody of bevacizumab (Avastin) and VEGF receptortyrosine kinase inhibitor (apatinib); antitumor immunotherapy, such asanti-PD-1 antibody (pembrolizumab, nivolumab), anti-PD-L1 antibody,anti-LAG-3 antibody, anti-CTLA-4 antibody, anti-4-1BB antibody,anti-GITR antibody, anti-ICOS antibody, interleukin 2.

Advantageous Effects

The pyrimidine or pyridine compounds of formula (I) of the presentinvention show a high inhibitory activity against one or more ofEGFR-activated mutant or resistant mutant and a relatively lowinhibition against a wild-type EGFR. The compounds of the presentinvention have a good physicochemical property and safety/toxicityparameter. Such compounds have a better clinical effect in the treatmentof disease (including cancer) mediated by EGFR-activated mutant and/ordrug-resistant mutant. Compared with AZD9291, such compounds have no oronly a relatively low level of AZ5104 (a demethylated metabolite ofAZD-9291) in animal in vivo experiments.

EXAMPLES

The following examples further illustrate the invention, but theseexamples are not to limit the scope of the invention.

Example 1

1. Synthesis of Intermediate 001-2

The intermediate 001-1 (10 g, 84.7 mmol) as the raw material wasdissolved in N,N-dimethylformamide (DMF) (500 mL) in a 1000 mLthree-necked flask under nitrogen (N₂) at room temperature, and theniodine (I₂) (21.5 g, 84.8 mmol) and potassium hydroxide (KOH) (19 g,338.6 mmol) were added sequentially, followed by stirring the reactionovernight at room temperature. After completion of the reaction, 200 mLof 10% sodium thiosulfate (Na₂S2O₃) was added to the reaction mixture,and ice water was used to quench the reaction. The mixture was extractedthree times with 500 mL of ethyl acetate (EA). The organic phases werecombined and washed once with 500 mL of saturated brine (NaCl), and theorganic phases were dried over anhydrous sodium sulfate (Na₂SO₄) andconcentrated to give 15.3 g of the intermediate 001-2 (74%) as anoff-white solid. Liquid Chromatography Mass Spectrometry (LCMS): 245.0.

2. Synthesis of Intermediate 001-3

Sodium hydride (NaH) (0.6 g, 14.8 mmol) was dissolved in 100 mL ofanhydrous tetrahydrofuran (THF) in a 250 mL three-necked flask under anitrogen atmosphere at room temperature. The reaction solution wascooled to 0° C. with ice brine, and then the intermediate 001-2 (3.0 g,12.3 mmol) was dissolved in 10 mL of anhydrous THF and added dropwisely.After the addition was completed, the temperature was raised to roomtemperature and the reaction mixture was stirred for 1 hour. Then, thereaction was cooled to 0° C., methyl iodide (Mel) (2 g, 14.76 mmol) wasadded dropwisely, and the reaction was maintained at room temperaturefor 3 hours. After the reaction was completed, 200 mL of ice water wasadded into the mixture to quench the reaction. The reaction mixture wasextracted three times with 500 mL of EA. The organic phases werecombined and then washed once with 100 mL of saturated brine. Theorganic phases were dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by chromatography (eluent: ethylacetate (EA):petroleum ether (PE)=1:5) to give 2.5 g of the intermediate001-3 (79%) as an off-white solid. LCMS: 259.0.

3. Synthesis of Intermediate 001-4

The intermediate 001-3 (2.5 g, 9.69 mmol) was dissolved in 300 mL of1,4-dioxane at room temperature in a 500 mL four-necked flask undernitrogen protection. 1,1,1,2,2,2-hexamethyldistannane (Me₃SnSnMe₃) (6.0g, 18.3 mmol) and tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄) (1.1g, 0.95 mmol) were added sequentially into the reaction mixture. Thetemperature was raised to 100° C., and the reaction mixture was stirredovernight. After the reaction was complete, the reaction system wascooled to room temperature. 15 mL of a potassium fluoride (KF) solution(1 M) and 50 mL of EA were added to quench the reaction and the reactionmixture was stirred at room temperature for 30 min. The mixture wasextracted three times with 100 mL of ethyl acetate and the organicphases were collected. The organic phases were combined and washed oncewith 100 mL of saturated brine. The organic phase was dried overanhydrous sodium sulfate and concentrated to dryness to give 930 mg ofthe intermediate 001-4 as a yellow oil. LCMS: 297.0.

4. Synthesis of Intermediate 001-6

Under a nitrogen atmosphere, the intermediate 001-4 (0.93 g, 3.15 mmol)was dissolved in 30 mL of 1,4-dioxane at room temperature in a 50 mLsingle-necked flask, and 2,4-dichloropyrimidine (001-5) (0.47 g, 3.15mmol) and tetrakis(triphenylphosphine)palladium (0.3 g, 0.26 mmol) wereadded to the reaction mixture. After the temperature was raised to 105°C., the reaction was stirred overnight. After the reaction was complete,the reaction system was cooled to room temperature with ice water andthe mixture was concentrated to dryness. The mixture was purified bycolumn chromatography (eluent: EA:PE=1:10) to give 480 mg of theintermediate 001-6 (62%) as a yellow oil. LCMS: 245.1.

5. Synthesis of Intermediate 001-8

The intermediate 001-7 (100 g, 708.5 mmol) and 800 mL of concentratedsulfuric acid (H₂S4) were added sequentially to a 2000 mL three-neckedflask under nitrogen protection and cooled to 0° C., and the reactiontemperature was maintained at a temperature between 0 and 10° C.Potassium nitrate (KNO₃) (71.6 g, 708.19 mmol) was added in batches for1 hour, and then the reaction was stirred overnight at room temperature.After completion of the reaction, 2 L of ice water was added to thethree-necked flask to quench the reaction. The reaction mixture wasadjusted to pH=10 with aqueous ammonia at low temperature and extractedthree times with 1 L of dichloromethane (DCM). Then, the organic phaseswere combined, washed three times with 3 L of saturated brine, driedover anhydrous sodium sulfate and rotovapped. The crude product waspurified by silica gel column chromatography (the used eluent, ethylacetate (EA) petroleum ether (PE)=1: 4-1:1) and eluent was rotovapped togive 79 g of the intermediate 001-8 (yield: 60%) as a yellow solid.LCMS: 187.0.

6. Synthesis of Intermediate 001-9

The intermediate 001-6 (480 mg, 1.96 mmol) was dissolved in 50 mL ofisopropanol (i-PrOH) at room temperature in a 100 mL single-neckedflask, and 001-8 (365 mg, 1.96 mmol) and p-toluenesulfonic acid (TsOH)(406 mg, 2.36 mmol) were added sequentially. The reaction was carriedout at 85° C. overnight. After the reaction was completed, the reactionsystem was cooled to room temperature with ice water and a solid wasprecipitated. The mixture was filtered and the solid was collected andwashed twice with 15 mL of isopropanol. The resulting solid was dried togive 450 mg of the intermediate 001-9 (58%) as yellow solid. LCMS:395.1.

7. Synthesis of Intermediate 001-11

The intermediate 001-9 (100 mg, 0.25 mmol) was dissolved inN-methylpyrrolidone (NMP) (25 mL) in a 50 mL single-necked flask, and1,1,4-N-trimethyl ethylenediamine (001-10) (33.7 mg, 0.33 mmol) andpotassium carbonate (K₂CO₃) (103.5 mg, 0.75 mmol) were addedsequentially. The temperature was raised to 85° C. for 2 h. After thereaction was complete, the mixture was cooled to room temperature. 70 mLof water was added to dilute the mixture and a solid was precipitated.The mixture was filtered, and the solid was collected and washed with 15mL of water three times and dried to give 180 mg of crude product. LCMS:477.2.

8. Synthesis of Intermediate 001-12

In a 100 mL single-necked flask, the intermediate 001-11 (180 mg, 0.38mmol) was dissolved in 30 mL of anhydrous methanol (MeOH) and palladiumon carbon (Pd/C) containing water (180 mg, 5% Pd), and ammonium formate(HCOONH₄) (180 mg) sequentially. The reaction was carried out at roomtemperature for 2.5 h. After the reaction was completed, the mixture wasfiltered, the filtrate was rotovapped and the mixture was dissolved in40 mL of DCM. The mixture was washed three times with 40 mL of saturatedbrine. The organic phases were combined, dried over sodium sulfate, androtovapped to give 157 mg of the intermediate 001-12 (93%) as a yellowsolid. LCMS: 447.3.

9. Synthesis of Compound 1

Compound 001-12 (157 mg, 0.32 mmol) was dissolved in 25 mL of anhydrousTHF in a 100 mL three-necked flask and diisopropylethylamine (DIPEA)(90.3 mg, 0.7 mmol) was added. The reaction system was cooled to 0° C.with ice water and acryloyl chloride (31.7 mg, 0.35 mmol) was added. Thereaction mixture was stirred at room temperature for 30 minutes. Afterthe reaction was completed, the reaction was quenched by addition of 2drops of water to the reaction system, the mixture was concentrated todryness, and the residue was purified by Prep-HPLC (column: WatersSunfire C18, 19×150 mm, 5 m; flow phase: acetonitrile (CH₃CN)/water(H₂O) (0.1% trifluoroacetic acid (TFA)); 15% acetonitrile to 35%acetonitrile; 7 min; 15 mL/min; detection wavelength: 254 nm). Theproduct fractions were collected and concentrated to remove most of theacetonitrile. An aqueous saturated sodium bicarbonate (NaHCO₃) solutionwas used to adjust the pH of the reaction system to 9 to 10 and thenextracted twice with 100 mL of DCM. The organic phases were combined anddried over anhydrous sodium sulfate to give the compound 1. LCMS: 501.3.

Compound 1 was dissolved in 10 mL of 0.1 N of hydrochloric acid (H) andfreeze dried to give 4 mg of the hydrochloride of compound 1(1.(HCl)_(n)) (2%) as a yellow solid. LCMS (parent molecule) C₂₇H₃₂N₈O₂:(ES, m/z): 501 [M+H]⁺. ¹H-NMR: (D₂O, 300 MHz, ppm): δ7.98-7.96 (m, 1H),7.83 (s, 1H), 7.74-7.72 (m, 1H), 7.39-7.30 (m, 2H), 7.15-7.13 (m, 1H),6.95 (s, 2H), 6.58-6.49 (m, 1H), 6.30-6.24 (m, 1H), 5.88-5.84 (m, 1H),3.88-3.81 (m, 6H), 3.41-3.36 (m, 2H), 3.28-3.17 (m, 2H), 2.80 (s, 6H),2.75 (s, 3H).

Example 2

1. Synthesis of Intermediate 002-2

The intermediate 001-5 (5.0 g, 33.6 mmol) was dissolved in 100 mL ofanhydrous tetrahydrofuran in a 250 mL three-necked flask at roomtemperature under a nitrogen atmosphere, and the intermediate 002-1 (3.0g, 25.2 mmol) and N,N-diisopropylethylamine (DIPEA) (8.6 g, 66.5 mmol)were added to the reaction system sequentially. The temperature wasraised to 70° C. and the reaction was stirred overnight. After thereaction was completed the next day, the reaction temperature was cooledto room temperature and the reaction solution was concentrated. Thecrude product was purified by silica gel column chromatography (eluent:PE/EA=50: 1-5:1), the product was collected to give 2.4 g of theintermediate 002-2 (31%) as a yellow solid. LCMS: 232.0.

2. Synthesis of Intermediate 002-3

The intermediate 002-2 (2.4 g, 10.4 mmol) was dissolved in 20 mL ofisopropanol a 100 mL three-necked flask at room temperature under anitrogen atmosphere, and the intermediate 001-8 (1.92 g, 10.3 mmol) andtoluenesulfonic acid (TsOH) (2.14 g, 12.4 mmol) were added to thereaction system sequentially. The temperature was raised to 105° C. andstirred for overnight. After the reaction was completed the next day,the reaction mixture was cooled to room temperature and a solid wasprecipitated. The solid was filtered by suction, and the filter cake wascollected and sequentially washed with 10 mL of isopropyl alcohol and 10mL of acetonitrile once, and then dried to give 1.4 g of theintermediate 002-3 (35%) as a yellow solid. LCMS: 382.1.

3. Synthesis of Intermediate 002-4

The intermediate 002-3 (1.0 g, 2.62 mmol) was dissolved inN-methylpyrrolidone (NMP) (20 mL) in a 50 mL single-necked flask at roomtemperature, and the intermediate 001-10 (280 mg, 2.74 mmol) andpotassium carbonate (K₂CO₃) (720 mg, 5.17 mmol) were added sequentially.The temperature was raised to 105° C. and stirred for 2 h. After thereaction was completed, the reaction solution was poured into 50 mL ofice water to quench the reaction. The mixture was extracted three timeswith 100 mL of ethyl acetate. The organic phases were combined andwashed once with 100 mL of saturated brine. The organic phases weredried over anhydrous sodium sulfate and concentrated to give 1.8 g ofcrude product 002-4 as a red oil. LCMS: 464.2.

4. Synthesis of Intermediate 002-5

The intermediate 002-4 (1.8 g, 3.88 mmol) was dissolved in 200 mL ofanhydrous methanol in a 50 mL single-necked flask at room temperature,and then palladium on carbon containing water (Pd/C) (1.0 g, 5% Pd) andammonium formate (5.0 g, 79.3 mmol) were sequentially added to thereaction mixture. Then, the reaction was carried out at room temperaturefor 2 hours. After the reaction was completed, the reaction mixture wasfiltered to remove Pd/C, and the filtrate was collected andconcentrated. The crude product was purified through silica gel columnchromatography (eluent: DCM/MeOH=50:1-5:1). The product was collectedand concentrated to give 810 mg of the intermediate 002-5 (48%) as a redoil. LCMS: 434.2.

5. Synthesis of Compound 2

The intermediate 002-5 (150 mg, 0.35 mmol) was dissolved in 8 mL ofanhydrous THF in a 50 mL three-necked flask at room temperature under anitrogen atmosphere, and DIPEA (89.2 mg, 0.69 mmol) was added and thereaction was cooled to 0° C. 2.0 mL of a solution of acryloyl chloride(001-13) (28.2 mg, 0.31 mmol) in THF was added dropwisely to thereaction mixture at 0° C., and the reaction was carried out at 0° C. for10 minutes. After the reaction was completed, the reaction system wasconcentrated directly. The crude product was purified by silica gelcolumn chromatography (eluent: DCM/MeOH=20:1-5:1). The resulting productwas collected and concentrated to give compound 2.

The compound 2 was re-dissolved in 3 mL of acetonitrile, andmethanesulfonic acid (MeSO₃H, or MsOH) (100 mg, 1.04 mmol) was addeddropwisely at room temperature. After the reaction was stirred at roomtemperature for 2 hours, a solid was precipitated. The solid wasfiltered by suction, and then filter cake was collected, washed twicewith 5 mL acetonitrile, frozen and dried to give 35.3 mg ofmethanesulfonate of compound 2 (13%) as a yellow solid.

LCMS (parent molecule) C₂₅H₂₉N₉O₂: (ES, m/z): 488 [M+H]⁺. ¹H-NMR: (300MHz, DMSO-D₆, ppm) δ 9.56 (s, 1H), 9.25-9.21 (m, 2H), 8.61-8.60 (d,J=5.4 Hz, 1H), 8.55-8.46 (m, 1H), 8.23-8.15 (m, 2H), 7.60-7.50 (m, 3H),7.05 (s, 1H), 6.71-6.62 (m, 1H), 6.31-6.30 (m, 2H), 5.80-5.77 (m, 1H),3.87 (s, 3H), 3.34-3.31 (m, 4H), 2.84-2.82 (d, J=4.8 Hz, 6H), 2.77 (s,3H), 2.36 (s, 9H).

Example 3

1. Synthesis of Intermediate 003-2

The intermediate 003-1 (3.0 g, 25.6 mmol) was dissolved in 150 mL of THFin a 500 mL of three-necked flask at room temperature under a nitrogenatmosphere, and the reaction was cooled to 0° C. Sodium hydride (NaH)(1.5 g, 40.3 mmol, 65%, stored in mineral oil) was added in batches tothe reaction mixture at 0° C. After the reaction was carried out for 20minutes, compound 001-5 was added into the reaction mixture at 0° C. andthe reaction was maintained for 2 hours. After the reaction wascomplete, the reaction was quenched with 200 mL of ice water and thereaction system was extracted three times with 200 mL of ethyl acetate.The organic phases were combined and washed once with 200 mL ofsaturated brine. The organic phases were dried over anhydrous sodiumsulfate and concentrated to dryness. Crude product was purified bysilica gel column chromatography (eluent: EA/PE=1:50-1:5) to give 3.5 gof intermediate 003-2 (38%) of a yellow solid. LCMS: 230.0.

2. Synthesis of Intermediate 003-3

The intermediate 003-2 (3.5 g, 15.2 mmol) was dissolved in 20 mL ofisopropanol in a 100 mL of single-necked flask at room temperature undera nitrogen atmosphere, and the intermediate 001-8 (2.84 g, 15.3 mmol)and TsOH (3.15 g, 18.3 mmol) were added to the reaction mixture. Thereaction temperature was raised to 105° C. and the reaction wasmaintained overnight with stirring. After the reaction was completed thenext day, the reaction system was cooled to room temperature and a solidwas precipitated. The reaction mixture was filtered, and filter cake wascollected and sequentially washed with 10 mL of isopropyl alcohol and 10mL of acetonitrile once, and then dried to give 1.5 g of theintermediate 003-3 (26%) as a yellow solid. LCMS: 380.1.

3. Synthesis of Intermediate 003-4

The intermediate 003-3 (1.5 g, 3.95 mmol) was dissolved in NMP (20 mL)in a 50 mL single-necked flask at room temperature, and the intermediate001-10 (410 mg, 4.01 mmol) and K₂C03 (1.1 g, 7.90 mmol) were added intothe reaction mixture. The temperature was raised to 105° C. and stirredfor 2 h. After the reaction was completed, 50 mL of ice water was usedto quench the reaction. The mixture was extracted three times with 100mL of ethyl acetate. The organic phases were combined and washed oncewith 100 mL of saturated brine. The organic phases were dried overanhydrous sodium sulfate and concentrated to give 0.6 g of compound003-4 (33%) as a red oil. LCMS: 462.2.

4. Synthesis of Intermediate 003-5

The intermediate 003-4 (600 mg, 1.30 mmol) was dissolved in 100 mL ofanhydrous methanol in a 50 mL single-necked flask at room temperature,and then palladium on carbon containing water (Pd/C) (0.5 g, 5% Pd) andammonium formate (2.0 g, 31.7 mmol) were added to the reaction mixture.Then, the reaction was carried out at room temperature for 2 hours andchecked that the reaction was completed. The reaction mixture wasfiltered, and the filtrate was collected and concentrated to dryness.The crude product was purified through silica gel column chromatography(eluent: DCM/MeOH=50:1-5:1) to give 200 mg of the intermediate 003-5(35%) as a yellow oil. LCMS: 432.2.

5. Synthesis of Compound 3

The intermediate 003-5 (110 mg, 0.25 mmol) was dissolved in THF (20 mL)in three-necked flask at room temperature under a nitrogen atmosphere,and DIPEA (65.8 mg, 0.51 mmol) was added into the reaction mixture andthe reaction was cooled to 0° C. A solution of acryloyl chloride (23.1mg, 0.26 mmol) in THF was added dropwisely to the reaction mixture at 0°C., and the reaction was carried out at 0° C. for 10 minutes. Thereaction mixture was concentrated, and the crude product was purifiedthrough silica gel column chromatography (eluent: DCM/MeOH=50:1-5:1) togive compound 3.

The product 3 was dissolved in 3 mL of acetonitrile, and methanesulfonicacid (73.4 mg, 0.76 mmol) was added dropwisely at room temperature andstirred at room temperature for 2 hours to precipitate a solid. Afterfiltration, the filter cake was collected and washed twice with 5 mL ofacetonitrile. After drying, 80 mg of compound 3 methanesulfonate (46%)was obtained as a yellow solid. LCMS (parent molecule) C₂₇H₃₁N₇O₂: (ES,m/z): [M+H]⁺=486.

¹H-NMR (300 MHz, DMSO-D₆, ppm): δ 9.50 (s, 2H), 9.27 (s, 1H), 8.47-8.43(d, J=12.9 Hz, 1H), 8.19-8.18 (m, 2H), 7.64-7.61 (m, 1H), 7.25-7.20 (m,1H), 7.18-7.13 (m, 2H), 7.08 (s, 1H), 6.89 (s, 2H), 6.73-6.67 (m, 1H),6.30-6.24 (m, 1H), 5.80-5.76 (m, 1H), 3.83 (s, 3H), 3.35 (s, 4H), 2.84(s, 6H), 2.73 (s, 3H), 2.37 (s, 6H).

Example 4

1. Synthesis of Intermediate 004-2

The intermediate 001-5 (3.0 g, 22.9 mmol) was dissolved in 150 mL ofanhydrous THF in a 500 mL three-necked flask at room temperature under anitrogen atmosphere, and the reaction was cooled to 0° C. NaH (65%,dispersed in mineral oil) (1.5 g, 22.9 mmol) was added in batches to thereaction mixture at 0° C. After the reaction was carried out for 20minutes, compound 004-1 (6.0 g, 40.3 mmol) was added at 0° C. and thereaction was maintained for 2 hours. After the reaction was complete,the reaction mixture was slowly poured into a 200 mL of ice water toquench the reaction and was extracted with 200 mL of ethyl acetate threetimes. The organic phases were combined and washed once with 100 mL ofsaturated brine, dried over anhydrous sodium sulfate, and concentrated.The crude product was purified through silica gel column chromatography(eluent: PE/EA=50/1-5/1) to give 3.5 g of intermediate 004-2 (36%) as ayellow solid. LCMS: 244.1.

2. Synthesis of Compound 4

The reactions from intermediate 004-2 to compound 4 and methanesulfonate(MsOH)₃ of compound 4 were completely the same as those from the secondstep to the fifth step in Example 3. Finally, 26.8 mg ofmethanesulfonate of compound 4 was obtained as a yellow solid. LCMS(parent molecule): C₂₈H₃₃N₇O₂ (ES, m/z): [M+H]⁺=500. ¹H-NMR (300 MHz,DMSO-D₆, ppm) δ 9.65 (s, 1H), 9.25 (s, 1H), 8.40-8.32 (m, 2H), 8.19 (m,1H), 7.64-7.61 (m, 1H), 7.25-7.20 (m, 1H), 7.18-7.13 (m, 3H), 7.08 (s,1H), 6.73-6.64 (s, 1H), 6.30-6.24 (m, 1H), 5.81-5.77 (d, J=12 Hz, 1H),3.88 (s, 3H), 3.34 (s, 4H), 2.84 (s, 6H), 2.83 (s, 3H), 2.35 (s, 10H),2.23 (s, 3H).

Example 5

1. Synthesis of Intermediate 005-2

The intermediate 001-5 (3.0 g, 25.2 mmol) was dissolved in 150 mL ofanhydrous THE in a 500 mL three-necked flask at room temperature under anitrogen atmosphere, and the reaction was cooled to 0° C. NaH (65%,dispersed in mineral oil) was added in batches to the reaction mixtureat 0° C. After the reaction was carried out for 20 minutes, compound001-5 was added at 0° C. and the reaction was maintained for 2 hours.After the reaction was complete, the reaction mixture was poured into a1.2 L of ice water to quench the reaction and was extracted with 200 mLof ethyl acetate three times. The organic phases were combined andwashed once with 200 mL of saturated brine and dried over anhydroussodium sulfate, then subjected to rotary evaporation. The crude productwas purified through silica gel column chromatography (eluent:PE/EA=50/1-5/1) to give 3.8 g of intermediate 005-2 (41%) as a yellowsolid. LCMS: 230.0.

2. Synthesis of Compound 5

The reactions from intermediate 005-2 to compound 5 and methanesulfonate(MsOH)₃ of compound 5 were completely the same as those from the secondstep to the fifth step in Example 3. Finally, 131.6 mg ofmethanesulfonate of compound 5 was obtained as a yellow solid. LCMS(parent molecule) C₂₇H₃₃N₇O₂: (ES, m/z): [M+H]⁺=488. ¹H-NMR (300 MHz,DMSO-D₆, ppm): δ 9.94 (s, 1H), 9.52 (s, 2H), 8.08 (s, 3H), 7.32-7.30 (m,1H), 7.08-7.05 (m, 2H), 6.82-6.73 (m, 1H), 6.56-6.54 (m, 1H), 6.26-6.21(m, 1H), 5.77-5.73 (m, 1H), 4.23-4.18 (m, 1H), 3.82 (s, 3H), 3.48-3.41(m, 4H), 3.26-3.17 (m, 2H), 2.83 (s, 6H), 2.68 (s, 3H), 2.37 (s, 9H).

Example 6

1. Synthesis of Intermediate 006-2

The intermediate 001-5 (1.3 g, 8.73 mmol), 13 mL of DME, FeCl₃ (1.414 g,8.72 mmol) and the intermediate 006-1 (974 mg, 7.43 mmol) were addedsequentially to a 100 mL three-necked flask under nitrogen atmosphere,and the reaction mixture was in an oil bath at 64° C. overnight. Afterthe reaction was completed, the reaction mixture was cooled to roomtemperature and filtered. The filter cake was washed three times with 20mL of methanol and the organic phases were combined, concentrated todryness and 1.0 g of intermediate 006-2 (47%) was obtained as a yellowsolid. LCMS: 244.1.

2. Synthesis of Intermediate 006-4

The intermediate 006-3 (100 g, 708.5 mmol) and 800 mL concentratedsulfuric acid (H₂SO₄) were sequentially added to a 2000 mL three-neckedflask under nitrogen atmosphere, and the reaction mixture was cooled to0° C. Potassium nitrate (KNO₃) (71.6 g, 708.2 mmol) was added in batchesat 0-10° C. for 1 h and then the reaction was maintained at roomtemperature for overnight. After the reaction was complete, 2000 mL ofice water was added to quench the reaction. The reaction mixture wasadjusted to pH 10 with aqueous ammonia at low temperature and extractedthree times with 1 L of dichloromethane (DCM). Then, the organic phaseswere combined, washed three times with 3 L saturated brine, dried overanhydrous sodium sulfate and then subjected to rotary evaporation. Thecrude product was purified by silica gel column chromatography (eluent,ethyl acetate (EA):petroleum ether (PE)=1:4-1:1) and eluent wasconcentrated to give 79 g of the intermediate 006-4 (60%) as a yellowsolid. LCMS: 187.0.

3. Synthesis of Intermediate 006-5

The intermediates 006-2 (75 mg, 307.8 mmol) and 006-4 (57.4 g, 308.4mmol), 975 mL of isopropyl alcohol, and p-toluenesulfonic acid (63.7 g,369.9 mmol) were sequentially added into a 2 L four-necked flask undernitrogen atmosphere, and the reaction was heated and maintained at 105°C. for 5 h. The reaction mixture was cooled to room temperature andfiltered, and the filter cake was washed with 750 mL of isopropanolthree times. The filter cake was washed three times with 750 mL ofacetonitrile and dried to give 75 g of the intermediate 006-5 (62%) as ayellow solid. LC-MS: 394.1.

4. Synthesis of Intermediate 006-7

The intermediates 006-5 (500 mg, 1.27 mmol) and 006-6 (147 mg, 1.65mmol) and K₂CO₃ (526 mg, 3.81 mmol) were added into a 50 mLsingle-necked flask, and NMP (20 mL) was added thereto at roomtemperature. Under nitrogen protection, the oil bath was heated to 100°C. After 2 h of reaction, the mixture was cooled to room temperature.The reaction solution was dropped into 100 mL of a mixture of ice andwater, and filtered by suction. The filter cake was collected, waswashed three times with 50 mL water and dried to give 430 mg of theintermediate 006-7 (68%) as a red solid. LC-MS: 463.2.

5. Synthesis of Intermediate 006-8

DCM MeOH=1:1 (20 mL) was added to a 250 mL single-necked flask at roomtemperature, followed by addition of the intermediate 006-7 (400 mg,0.86 mmol), ammonium formate (400 mg, 6.34 mmol) and palladium on carboncontaining water (400 mg, 5% Pd). The reaction was carried out at roomtemperature for 3 h. The reaction mixture was filtered, and the filtratewas collected and subjected to rotary evaporation to give a crudeproduct which was purified by silica gel column chromatography (eluent:DCM) to give 350 mg of the intermediate 006-8 (94%) as a pale red solid.LC-MS: 433.2.

6. Synthesis of Final Product 6

Anhydrous ethanol (20 mL) was added into a 100 mL three-necked flask atroom temperature, and then the intermediate 006-8 (340 mg, 0.787 mmol)and DIPEA (203 mg, 1.57 mmol) were added. The reaction mixture wascooled to 0° C. in an ice-water bath followed by dropping acryloylchloride (70 mg, 0.787 mmol). The reaction was carried out at 0° C. for2 h, and then was quenched by adding 2 mL of water. The reaction mixturewas subjected to rotary evaporation to give a crude product which waspurified by silica gel column chromatography (eluent: DCM:MeOH=30:1).Eluent was concentrated to give compound 6.

The product 6 was dissolved in 4 mL of acetonitrile. Excess ofconcentrated hydrochloric acid was added dropwisely and the resultingmixture was concentrate directly. The crude was subjected to freezedrying to give 26.3 mg of hydrochloride of the product 6 (6%) as ayellow solid. LCMS (parent molecule) C₂₇H₃₀N₆O₃ (ES, m/z): [M+H]+=487.¹H-NMR (300 MHz, D₂O, ppm) δ 3.13 (s, 3H), 3.21 (s, 3H), 3.32-378 (m,7H), 3.89 (s, 3H), 5.87-5.90 (d, J=11.4 Hz, 1H), 6.32-6.41 (m, 2H),6.74-6.77 (d, J=6.0 Hz, 1H), 6.91-6.94 (m, 1H), 7.13-7.27 (m, 3H),7.57-7.65 (m, 2H), 7.90 (s, 1H), 7.99 (s, 1H).

Example 7

1. Synthesis of Intermediate 007-2

The intermediate 006-5 (100 mg, 1.78 mmol), NMP (30 mL), potassiumcarbonate (0.5 g, 3.56 mmol) and the intermediate 007-1 (0.268 g, 2.31mmol) were added into a 100 mL single-necked flask and the reaction wascarried out at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature followed by addition of 70 mL of water to quench thereaction. A solid was precipitated and undergone a sucking filtration,and the filter cake was collected and washed with 20 mL of water 3 timesand then dried to give 600 mg of the intermediate 007-2 (69%) as a redsolid. LC-MS: 490.2.

2. Synthesis of Intermediate 007-3

The intermediate 007-2 (600 mg, 1.22 mmol), anhydrous methanol (100 mL),palladium on carbon containing water (600 mg, 5% Pd) and ammoniumformate (600 mg) were added into a 250 mL single-necked flasksequentially. After the reaction was stirred for 3 h, the reactionmixture was filtered and the filtrate was collected and subjected torotary evaporation. The crude product was dissolved with 150 mL of DCM,and then washed with 50 mL of saturated brine solution. The organicphases were dried over sodium sulfate and concentrated to give 400 mg ofthe intermediate 007-3 (71%) as a pale yellow solid. LC-MS: 460.3.

3. Synthesis of Compound 7

The intermediate 007-3 (400 mL, 0.871 mmol), anhydrous THF (40 mL) andDIPEA (0.224 g, 1.74 mmol) were sequentially added into a 100 mLthree-necked flask at room temperature, then the reaction mixture wascooled to 0° C. and the intermediate 001-13 (78 mg, 0.871 mmol) wasadded thereto. The reaction temperature was raised to room temperatureand the reaction was stirred for 30 min. After adding 3 drops of water,the system was directly subjected to rotary evaporation and the crudeproduct was purified by prep-HPLC (column, Waters Sunfire C18, 19×150mm, 5 um; flow phase, acetonitrile/water (0.1% trifluoroacetic acid(TFA)), 15% to 35%, 7 min; flow rate 20 mL/min; detection wavelength,254 nm). The product was collected and concentrated to give the compound7.

The compound 7 was dissolved in 15 mL of acetonitrile, andmethanesulfonic acid (35 mg, 2.6 mmol) was added. After stirring for 2 hat room temperature, a solid was precipitated and the mixture wasfiltered by suction. The solid cake was collected and dried to give 49.8mg of sulfonate of the compound 7 (7%) as a yellow solid. LCMS (parentmolecule) C₂₉H₃₅N₇O₂ (ES, m/z) [M+1]⁺: 514. H-NMR (D₂O, 300 MHz, ppm) δ1.15-1.20 (m, 3H), 2.68-2.79 (m, 16H), 3.11-3.18 (m, 3H), 3.33-3.38 (m,5H), 3.84 (s, 5H), 5.87-5.91 (d, J=10.8 Hz, 1H), 6.25-6.31 (d, J=16.8Hz, 1H), 6.54-6.60 (m, 2H), 6.97 (s, 2H), 7.13 (m, 2H), 7.32 (m, 1H),7.78 (m, 2H).

Example 8

1. Synthesis of Intermediate 008-2

The intermediates 006-5 (1.0 g, 2.54 mmol) and 008-1 (0.430 mg, 3.31mmol) and K₂C3 (1.05 g, 7.63 mmol) were sequentially added into a 50 mLsingle-necked flask, and NMP (20 mL) was added thereto at roomtemperature. Under nitrogen protection, it was heated to 100° C. in oilbath. After 2 h of reaction, the mixture was cooled to room temperature.The reaction solution was dropped into 100 mL of a mixture of ice andwater, and filtered by suction. The filter cake was collected, washedthree times with 50 mL water and dried to give 0.8 g of the crudeproduct 008-2 as a red solid.

2. Synthesis of Intermediate 008-3

DCM/MeOH (1:1, 20 mL) was added to a 250 mL single-necked flask at roomtemperature, followed by the addition of the intermediate 008-2 (800 mg,2.38 mmol), ammonium formate (800 mg, 12.7 mmol) and palladium on carboncontaining water (0.800 g, 5% Pd). The reaction mixture was stirred atroom temperature for 3 h. The reaction mixture was filtered, and thefiltrate was collected and subjected to rotary evaporation to give acrude product which was purified by silica gel column chromatography(eluent: DCM/MeOH=30:1). Eluents were combined and concentrated to give0.650 g of the intermediate 008-3 (86%) as a pale red solid.

3. Synthesis of Compound 8

Anhydrous ethanol (20 mL) was added into a 100 mL three-necked flask atroom temperature, and then the intermediate 008-3 (300 mg, 0.63 mmol)and DIPEA (163 mg, 1.27 mmol) were added thereto. The reaction mixturewas cooled to 0° C. in an ice-water bath followed by addition of asolution of acryloyl chloride (56 mg, 0.6 mmol) in 2 mL of anhydrousTHF. The reaction was stirred at 0° C. for 1 h, and then was quenched byadding 2 mL of water. The reaction mixture was subjected to rotaryevaporation to give a crude product which was purified by silica gelcolumn chromatography (eluent: DCM/MeOH=30:1). Eluents were combined andconcentrated to give compound 8.

The compound 8 was dissolved in 4 mL of anhydrous acetonitrile, and asolution of methanesulfonic acid (65.6 mg, 6.8 mmol) was addeddropwisely. After the reaction was carried out for 2 h at roomtemperature, a yellow solid was precipitated and the mixture wasfiltered by suction. The solid cake was collected and dried to give 53mg of sulfonate of the compound 8 (7%) as a yellow solid. LCMS (parentmolecule) C₃₀H₃₇N₇O₂ (ES, m/z): [M+H]⁺=528. ¹H-NMR (300 MHz, DMSO-D₆,ppm) δ 9.85-9.86 (m, 1H), 9.55-9.64 (m, 1H), 8.73 (s, 1H), 8.26 (s, 3H),7.57-7.60 (d, J=8.1 Hz, 1H), 7.37-7.39 (m, 2H), 7.29-7.28 (m, 1H), 7.05(s, 1H), 6.82-6.95 (m, 1H), 6.29 (s, 1H), 5.75-5.79 (d, J=12.3 Hz, 1H),3.92 (s, 3H), 3.89 (s, 3H), 3.27 (m, 4H), 3.15 (m, 4H), 2.69 (s, 3H),2.31 (s, 3H), 1.17-1.22 (m, 6H).

Example 9

1. Synthesis of Intermediate 009-2

The intermediate 006-5 (1.0 g, 2.54 mmol), 009-1 (0.383 g, 3.31 mmol)and K₂C03 (1.05 g, 7.63 mmol) were added to a 50 mL single-necked flaskat room temperature, followed by that NMP solvent (20 mL) was added. Thetemperature of oil bath was raised to 100° C. for 2h. The reaction wascooled to room temperature and the reaction mixture was dropped into 100mL of mixture contain ice and water. The reaction mixture undergone asucking filtration and the filter cake was collected. The filter cakewas washed with 50 mL of water 3 times and dried to give 650 mg ofcompound 009-2 (35%) as a red solid. LC-MS: 490.3.

2. Synthesis of Compound 9

The chemical reactions from intermediate 009-2 to compound 9 andmethanesulfonate (MsOH)₃ of compound 9 were completely the same as thosefrom the second step to the third step in Example 8. Finally, 29.3 mg ofmethanesulfonate of compound 9 (13%) was obtained as a yellow solid.LCMS (parent molecule) C₂₉H₃₅N₇O₂ (ES, m/z): (ES, m/z): [M+H]⁺=514.¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 0.95-1.00 (m, 3H), 2.27-2.34 (m, 6H),2.81-2.82 (m, 6H), 3.0-3.07 (m, 2H), 3.23-3.31 (m, 2H), 3.35-3.42 (m,2H), 3.86 (s, 3H), 3.93 (s, 3H), 5.80 (d, J=12 Hz, 1H), 6.27-6.32 (d,J=17.1 Hz, 1H), 6.69-6.78 (m, 1H), 7.08 (s, 1H), 7.14-7.19 (m, 1H),7.27-7.33 (m, 1H), 7.41-7.43 (d, J=6.3 Hz, 1H), 7.58-7.61 (d, J=8.4 Hz,1H), 8.25-8.29 (m, 1H), 8.79 (s, 1H), 9.42-9.43 (d, J=2.7 Hz, 1H).

Example 10

1. Synthesis of Compound 10

The reaction steps and conditions for synthesizing compound 10 andmethanesulfonate (MsOH)₃ of compound 10 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 010-1 in the first step.Finally, 64 mg of methanesulfonate of compound 10 was obtained as ayellow solid. LCMS (parent molecule) C₂₇H₃N₆O₄S (ES, m/z): (ES, m/z):535 [M+1]⁺. ¹H-NMR (DMSO-D₆, ppm) δ 2.34 (s, 9H), 2.74 (s, 3H), 3.06 (s,3H), 3.48-3.29 (m, 4H), 3.83 (s, 3H), 3.94 (s, 3H), 5.76-5.72 (m, 1H),6.24-6.18 (m, 1H), 6.66-6.57 (m, 1H), 7.29-7.15 (m, 2H), 7.42-7.32 (m,1H), 7.44-7.42 (m, 1H), 7.62-7.59 (m, 1H), 8.40-8.20 (m, 2H), 8.48-8.40(m, 1H), 8.85 (s, 1H), 9.34 (s, 1H), 10.14 (s, 1H).

Example 11

1. Synthesis of Intermediate 011-3

The reaction steps and conditions for synthesizing compound 011-3 werecompletely the same as those from the first step to the second step inExample 8, except that the intermediate 008-1 as a raw material in thefirst step of the example 8 was replaced with the intermediate 010-1 inthe first step. Finally, compound 011-3 was obtained as a red solid.

2. Synthesis of Compound 11

THF (20 mL), H₂O (2 mL), intermediate 011-3 (200 mg, 0.44 mmol) weresequentially added into a 250 mL single-necked flask at roomtemperature. The reaction system was cooled to 0° C., followed by theaddition of 3-chloropropionyl chloride (66.7 mg, 0.53 mmol). After thereaction temperature was raised to the room temperature, the reactionwas stirred for 1 h and was extracted twice with 50 mL of EA. Theorganic phases were collected, and then washed once with 30 mL of sodiumbicarbonate (NaHCO₃) and washed twice with 40 mL of saturated saltwater. After concentrated to dryness, the organic phases were dissolvedin a 250 mL single-necked flask and triethylamine (Et₃N) (132 mg, 1.30mmol) was added thereto. Then, the reaction system was heated to refluxfor 2 h. The reaction mixture was cooled and concentrated to removeacetonitrile, and finally the crude product was purified by prep-HPLC:(column, Waters X-Bridge RP18, 19×150 mm, Sum; eluent: phase A: water(0.05% TFA), phase B: acetonitrile; elution gradient: 15% B-45% B, 7min; flow rate 20 mL/min; detection wavelength, 254 nm). The product wascollected and concentrated to remove the most of acetonitrile, and thenfreeze-dried to give 20 mg of compound 11.

The product 11 (20 mg) was dissolved in acetonitrile (2 mL), and asolution (2 mL) of methanesulfonic acid (75.0 mg) in acetonitrile wasadded dropwisely thereto. After the reaction mixture was stirred at roomtemperature for 2 h, a yellow solid was precipitated. The reactionmixture underwent a sucking filtration, and the filter cake wascollected and re-dissolved with distilled water and freeze dried to give23.1 mg of methanesulfonate of compound 11 as a yellow solid. LCMSLCMS(parent molecule) C₂₉H₃₃N₇₂ (ES, m/z): (ES, m/z): 512 [M+H]⁺. ¹H-NMR:(300 MHz, DMSO-D₆, ppm) δ 2.32 (s, 6H), 2.63 (s, 3H), 3.18-3.20 (m, 2H),3.37-3.39 (m, 2H), 3.87-3.92 (s, 3H), 3.95-3.98 (s, 3H), 4.05-4.14 (m,4H), 5.81-5.84 (d, J=9 Hz, 1H), 6.30-6.35 (d, J=17.1 Hz, 1H), 6.72-6.31(m, 1H), 7.01 (s, 1H), 7.15-7.17 (m, 1H), 7.20-7.35 (m, 2H), 7.56-7.59(d, J=8.4 Hz, 1H), 8.28 (br s, 2H), 8.51 (br s, 1H), 8.68 (br s, 1H),9.50 (br s, 1H), 9.70-9.73 (m, 1H).

Example 12

1. Synthesis of Compound 12

The reaction steps and conditions for synthesizing compound 12 and themethanesulfonate (MsOH)₂ of compound 12 were completely the same asthose from the first step to the third step in Example 7, except thatthe intermediate 007-1 as a raw material in the first step of theexample 7 was replaced with the intermediate 012-1 in the first step.Finally, 180 mg of methanesulfonate of compound 12 was obtained as ayellow solid. LCMSLCMS (parent molecule) C₃₀H₃₅N₇O₂ (ES, m/z): 526[M+1]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ 1.91-2.01 (m, 4H), 2.33 (s,7H), 2.73-2.71 (m, 3H), 3.01-3.08 (m, 2H), 3.57-3.35 (m, 5H), 3.86 (s,3H), 3.93 (s, 3H), 5.83-5.79 (m, 1H), 6.30-6.24 (m, 1H), 6.73-6.65 (m,1H), 7.01 (s, 1H), 7.19-7.17 (m, 1H), 7.30-7.27 (m, 1H), 7.61-7.58 (m,1H), 8.30-8.23 (m, 3H), 8.76 (s, 1H), 9.41 (s, 1H), 9.63 (s, 1H).

Example 13

1. Synthesis of Compound 13

The reaction steps and conditions for synthesizing compound 13 andmethanesulfonate (MsOH)₂ of compound 13 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 013-1 in the first step.Finally, 97.5 mg of methanesulfonate (MsOH)₂ of compound 13 was obtainedas a yellow solid. LCMSLCMS (parent molecule) C₃₀H₃₅N₇O₂(ES, m/z):[M+H]⁺=526. ¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 2.00-2.15 (m, 4H), 2.498(m, 6H), 2.74-2.81 (m, 6H), 2.87 (s, 1H), 3.12-3.43 (m, 4H), 3.82 (s,3H), 3.94 (s, 3H), 5.73-5.77 (d, J=11.4 Hz, 1H), 6.20-6.26 (m, 1H),6.70-6.79 (m, 1H), 6.97 (s, 1H), 7.19-7.21 (m, 1H), 7.29-7.34 (m, 1H),7.42-7.44 (d, J=6.9 Hz, 1H), 7.59-7.62 (d, J=8.1 Hz, 1H), 8.23 (s, 3H),8.84 (s, 1H), 9.21 (s, 1H), 10.40 (s, 1H), 10.43 (s, 1H).

Example 14

1. Synthesis of Compound 14

The reaction steps and conditions for synthesizing compound 14 andmethanesulfonate (MsOH)₃ of compound 14 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 014-1 in the first step.Finally, 0.125 g of methanesulfonate (MsOH)₂ of compound 14 was obtainedas a yellow solid. LCMSLCMS (parent molecule) C₃₁H₃₅N₇O₂(ES, m/z):[M+H]⁺=538. ¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 10.01 (m, 2H), 9.19 (s,1H), 8.82 (s, 1H), 8.22 (s, 3H), 7.62-7.59 (d, J=8.1 Hz, 1H), 7.43-7.41(d, J=6.9 Hz, 1H), 7.34-7.29 (m, 1H), 7.22-7.19 (m, 1H), 6.96 (s, 1H),6.69-6.59 (m, 1H), 6.25-6.19 (m, 1H), 5.77-5.73 (d, J=10.2 Hz, 1H),4.21-4.04 (m, 4H), 3.94 (s, 3H), 3.83 (s, 3H), 3.55-3.43 (m, 2H),3.28-3.17 (m, 2H), 2.80-2.72 (m, 2H), 2.51 (s, 9H), 2.35-2.27 (m, 1H),2.07-2.03 (m, 2H), 1.73-1.66 (m, 2H), 1.23 (s, 1H).

Example 15

1. Synthesis of Compound 15

The reaction steps and conditions for synthesizing compound 15 andmethanesulfonate (MsOH)₃ of compound 15 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 015-1 in the first step.Finally, 139.7 mg of methanesulfonate (MsOH)₂ of compound 15 wasobtained as a brown solid. LCMSLCMS (parent molecule) C₃₂H₃₇N₇O₂ (ES,m/z):(ES, m/z): [M+H]⁺=552. ¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 1.90-1.99(m, 4H), 2.05-2.10 (m, 2H), 2.15-2.19 (m, 2H), 2.27-2.32 (m, 7H),2.72-2.83 (m, 2H), 3.09-3.21 (m, 4H), 3.26-3.29 (m, 2H), 3.83 (s, 3H),3.93 (s, 1H), 5.74-5.78 (m, 1H), 6.21-6.26 (d, J=15.6 Hz, 1H), 6.60-6.69(m, 1H), 6.95 (s, 1H), 7.16-7.21 (m, 1H), 7.28-7.31 (m, 1H), 7.33-7.40(m, 1H), 7.58-7.61 (d, J=7.8 Hz, 1H, 8.22-8.33 (m, 3H), 8.78 (s, 1H),9.19 (s, 1H), 9.64 (s, 1H).

Example 16

1. Synthesis of Compound 16

The reaction steps and conditions for synthesizing compound 16 andmethanesulfonate (MsOH)₃ of compound 16 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 016-1 in the first step.Finally, 67.3 mg of methanesulfonate (MsOH)₃ of compound 16 was obtainedas a yellow solid. LCMSLCMS (parent molecule) C₃₃H₄₀N₈O₂ (ES, m/z):[M+H]⁺=581. ¹H-NMR (300 MHz, D₂O, ppm) δ 1.89-1.92 (m, 2H), 2.25-2.28(m, 2H), 2.74 (s, 9H), 2.79-2.87 (m, 2H), 2.96-3.00 (s, 3H), 3.19 (m,2H), 3.45-3.66 (m, 4H), 3.66 (m, 10H), 3.80 (s, 3H), 5.86-5.91 (d,J=10.5 Hz, 1H), 6.23-6.29 (d, J=17.1 Hz, 1H), 76.48-6.57 (m, 2H), 6.86(s, 1H), 7.02 (s, 1H), 7.19 (s, 2H), 7.35 (br s, 1H), 7.55 (brs, 1H),7.90 (br s, 2H).

Example 17

1. Synthesis of Compound 17

The reaction steps and conditions for synthesizing compound 17 andmethanesulfonate (MsOH)₂ of compound 17 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 017-1 in the first step.Finally, 130.7 mg of methanesulfonate (MsOH)₂ of compound 17 wasobtained as a yellow solid. LCMSLCMS (parent molecule) C₂₈H₃₀N₆O₃ (ES,m/z): [M+H]⁺=499. ¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 2.08 (m, 2H), 2.35(s, 6H), 3.22 (m, 2H), 3.26 (s, 3H), 3.42-3.60 (m, 2H), 3.82 (s, 3H),3.94 (s, 3H), 4.06 (s, 1H), 5.69-5.72 (d, J=10.2 Hz, 1H), 6.17-6.22 (d,J=15.6 Hz, 1H), 6.47-6.57 (m, 2H), 7.26-7.49 (m, 4H), 7.60-7.62 (d,J=8.1 Hz, 1H), 8.18 (br s, 1H), 8.18 (s, 1H), 9.51 (s, 1H).

Example 18

1. Synthesis of Compound 18

The reaction steps and conditions for synthesizing compound 18 andmethanesulfonate (MsOH)₃ of compound 18 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 018-1 in the first step.LCMSLCMS (parent molecule) C₃₀H₃₃N₇O₂(ES, m/z): (ES, m/z): [M+H]⁺=524.¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 11.29 (s, 1H), 9.83 (s, 1H), 8.82 (s,1H), 8.15 (br s, 1H), 7.618-7.59 (d, J=8.1 Hz, 1H), 7.41-7.39 (d, J=6.9Hz, 1H), 7.39-7.30 (m, 2H), 7.11-7.05 (m, 1H), 6.79 (s, 1H), 6.23-6.17(m, 1H), 5.72-5.68 (m, 1H), 4.16-4.18 (m, 2H), 4.08-4.03 (m, 4H), 3.94(s, 3H), 3.82 (s, 3H), 3.67 (m, 1H), 3.67-3.35 (m, 1H), 3.25-3.31 (m,1H), 2.76-72.72 (m, 1H), 2.49-2.41 (m, 1H), 2.33 (s, 9H), 2.27-2.26 (m,2H), 1.97-1.91 (m, 1H), 1.29-1.23 (m, 2H).

Example 19

1. Synthesis of Compound 19

The reaction steps and conditions for synthesizing compound 19 andmethanesulfonate (MsOH)₃ of compound 19 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 019-1 in the first step.LCMSLCMS (parent molecule) C₃₁H₃₅N₇O₂ (ES, m/z): (ES, m/z): [M+H]⁺=538.¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 11.15 (s, 1H), 9.78 (s, 1H), 8.80 (s,1H), 8.37-8.03 (m, 2H), 7.61-7.58 (d, J=8.1 Hz, 1H), 7.61-7.24 (m, 3H),7.04-6.95 (m, 1H), 6.80 (s, 1H), 6.22-6.17 (d, J 13.2 Hz, 1H), 5.71-5.67(d, J=12.3 Hz, 1H), 3.93 (s, 4H), 3.83 (s, 3H), 3.62-3.52 (m, 5H),3.14-3.10 (n, 2H), 3.00-2.92 (m, 1H), 2.49 (s, 5H), 2.06-1.96 (m, 4H).

Example 20

1. Synthesis of Compound 20

The reaction steps and conditions for synthesizing compound 20 andmethanesulfonate (MsOH)₃ of compound 20 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 020-1 in the first step.LCMS (parent molecule) C₃₂H₃₈N₈O₂ (ES, m/z): (ES, m/z): [M+H]⁺=567.¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 2.36 (s, 1H), 2.58 (s, 12H), 2.89 (s,3H), 3.25-3.22 (m, 2H), 3.57-3.46 (m, 5H), 3.72-3.70 (m, 8H), 3.84 (s,3H), 3.94 (s, 3H), 5.72-5.68 (m, 1H), 6.22-6.17 (m, 1H), 6.79-6.71 (m,2H), 7.39-7.23 (m, 2H), 7.41-7.39 (m, 1H), 7.62-7.59 (m, 1H), 8.23-8.15(m, 1H), 8.80 (s, 1H), 9.53 (s, 1H).

Example 21

1. Synthesis of Compound 21

The reaction steps and conditions for synthesizing compound 21 andmethanesulfonate (MsOH)₃ of compound 21 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 021-1 in the first step.LCMSLCMS (parent molecule) C₂₇H₂₈N₆O₃ (ES, m/z): (ES, m/z): [M+H]⁺=485.

¹H-NMR (300 MHz, DMSO-D₆, D₂O, ppm) δ 2.37 (m, 6H), 3.25 (s, 3H),3.70-3.75 (m, 2H), 3.82 (s, 3H), 3.94 (s, 3H), 4.14-4.19 (m, 2H),4.25-4.32 (m, 1H), 5.76-5.72 (m, 1H), 6.15-6.23 (m, 2H), 6.2 (s, 1H),6.45-6.50 (m, 1H), 7.35-7.39 (m, 4H), 7.60-7.63 (d, J=8.1 Hz, 1H), 8.10(m, 1H), 8.74 (s, 1H).

Example 22

1. Synthesis of Intermediate 022-3

The intermediate 022-1 (10 g, 42.1 mmol) as raw material was dissolvedin 100 mL of dichloromethane in a 250 mL three-necked flask at roomtemperature under a nitrogen atmosphere, and cyclobutylaminehydrochloride (4.7 g, 50.2 mmol) was added thereto. Then, the reactionwas carried out for 1h at room temperature, followed by that thereaction mixture was cooled to 0° C. Sodium triacetoxyborohydride (13.4g, 63.2 mmol) was added to the reaction system in batches, and thereaction temperature was raised to room temperature and the reaction wasstirred overnight. The reaction system was adjusted to pH 8-9 withanhydrous sodium carbonate aqueous solution the next day, and themixture was extracted three times with 200 mL of methylene chloride. Theorganic phases were combined and washed once with 300 mL of saturatedbrine. The organic phases were dried over anhydrous sodium sulfate andconcentrated. The crude product was purified by silica gel columnchromatography (eluent: EA/PE=1:5) to give 4.7 g of intermediate 022-3as a yellow oil. LCMS: 279.2.

2. Synthesis of Intermediate 022-4

The intermediate 022-3 (3 g, 10.8 mmol) as raw material was dissolved in30 mL of anhydrous methanol in a 100 mL single-necked flask at roomtemperature. Palladium on carbon containing water (3 g, 5% Pd) was addedand the reaction system was exchanged with hydrogen 3 times. Thereaction was carried out overnight at room temperature under hydrogen.After the reaction was completed, the mixture was filtered by suctionand the filtrate was collected and concentrated to give 1.2 g of crudeproduct 022-4 as yellow oil. LCMS: 113.1.

3. Synthesis of Intermediate 022-6

The reaction steps and conditions for synthesizing compound 022-6 werecompletely the same as those from the first step to the second step inExample 8, except that the intermediate 008-1 as a raw material in thefirst step of the example 8 was replaced with the intermediate 022-4 inthe first step. LCMS: 445.3.

4. Synthesis of Compound 22

The intermediate 022-6 (250 mg, 0.55 mmol) as raw material was dissolvedin 50 mL of anhydrous THF in a 100 mL single-necked flask at roomtemperature under a nitrogen atmosphere, and N,N-diisopropylethylamine(DIPEA) (141.8 mg, 1.10 mmol) was added thereto. After the reactionmixture was cool to 0° C., acryloyl chloride (48.9 mg, 0.540 mmol) wasadded dropwisely to the reaction system at 0° C. The reaction system washeated to room temperature, and stirred for 1 h. After the reaction wascompleted, the reaction was quenched by the addition of 2 mL of waterand the mixture was concentrated to dryness. The resulting residue waspurified by prep-HPLC (column: Xbridge Prep RP C15 um 8, 19×150 mm;mobile phase: 0.05% ammonia+10 mmol of ammoniumbicarbonate)/acetonitrile; 77% acetonitrile to 81% acetonitrile, 4 min;5 mL/min; detection wavelength: 254 nm), concentrated and freeze driedto give 9.8 mg of product 22 (4%) as a yellow solid. LCMS (parentmolecule) C₂₉H₃₁N₇O₂: (ES, m/z): 510 [M+H]⁺. ¹H-NMR: (DMSO-D₆, 300 MHz,ppm) δ 9.29 (s, 1H), 8.34-8.32 (m, 2H), 8.26-8.24 (d, J=5.4 Hz, 1H),7.92 (s, 1H), 7.76 (s, 1H), 7.51-7.49 (m, 1H) 7.23-7.16 (m, 2H),7.13-7.12 (d, J=5.1 Hz, 2H), 6.55-6.46 (m, 1H), 6.22 (s, 1H), 6.17-6.16(d, J=2.1 Hz, 1H), 5.70-5.66 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H),3.60-3.3.55 (m, 2H), 3.41-3.34 (m, 1H), 3.17-3.13 (t, J=6.9 Hz, 4H),2.00-1.95 (m, 2H).

Example 23

1. Synthesis of Intermediate 023-3

The reaction steps and conditions for synthesizing compound 023-3 werecompletely the same as those from the first step to the second step inExample 8, except that the intermediate 008-1 as a raw material in thefirst step of the example 8 was replaced with the intermediate 023-1 inthe first step. LCMS: 470.3.

2. Synthesis of Compound 23

The reaction steps and conditions for synthesizing compound 23 weresubstantially the same as those of the fourth step to the second step inExample 22. LCMSLCMS (parent molecule) C₃₀H₃₃N₇O₂: (ES, m/z): 524[M+H]⁺. ¹H-NMR: (DMSO-D₆, 300 MHz, ppm) δ 9.32 (s, 1H), 8.35-8.32 (m,2H), 8.25-8.23 (d, J=5.4 Hz, 1H), 7.94 (s, 2H), 7.77 (s, 1H), 7.51-7.48(d, J=8.4 Hz, 1H), 7.23-7.11 (m, 3H), 6.56-6.47 (m, 1H), 6.25-6.17 (m,2H), 5.70-5.67 (m, 1H), 3.96 (m, 1H), 3.87-3.84 (d, J=8.7 Hz, 6H), 3.66(m, 2H), 2.50-2.43 (m, 4H), 1.71 (s, 4H), 1.23 (s, 1H).

Example 24

1. Synthesis of Compound 24

The reaction steps and conditions of compound 24 and themethanesulfonate (MsOH)₃ of compound 24 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 024-1 in the first step.LCMSLCMS (parent molecule) C₃₁H₃₆N₈O₂(ES, m/z): (ES, m/z): [M+H]⁺=553.¹H-NMR (300 MHz, D₂O, ppm) δ 2.68-2.76 (m, 11H), 2.91 (s, 3H), 2.98-3.10(m, 3H), 3.36-3.56 (m, 8H), 3.70 (s, 1H), 3.74-3.90 (m, 5H), 4.12-4.17(m, 2H), 5.90-5.94 (d, J=10.8 Hz, 1H), 6.30-6.35 (m, 2H), 6.45-6.54 (m,2H), 7.04 (m, 1H), 7.19-7.23 (m, 2H), 7.33-7.35 (m, 1H), 7.68-7.72 (m,2H).

Example 25

1. Synthesis of Compound 25

The reaction steps and conditions of compound 25 and themethanesulfonate (MsOH)₃ of compound 25 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 025-1 in the first step.LCMSLCMS (parent molecule) C₃₀H₃₃N₇O₃ (ES, m/z): (ES, m/z): [M+H]⁺=540.¹H-NMR (300 MHz, D₂O, ppm) δ 2.72 (s, 6H), 3.20-3.28 (m, 4H), 3.63 (s,3H), 3.81 (s, 3H), 3.93-4.02 (m, 6H), 4.09-4.11 (m, 1H), 4.21-4.27 (m,2H), 5.87-5.91 (d, J=11.4 Hz, 1H), 6.28-6.51 (m, 3H), 6.84-6.86 (d,J=6.9 Hz, 1H), 7.12-7.15 (m, 1H), 7.23-7.34 (m, 2H), 7.37-7.60 (m, 1H),7.88-7.95 (m, 2H).

Example 26

1. Synthesis of Compound 26

The reaction steps and conditions of compound 26 and themethanesulfonate (MsOH)₃ of compound 26 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 026-1 in the first step.LCMS C₃₁H₃₅N₇O₃: (ES, m/z): 554 [M+H]⁺.

¹H-NMR: (300 MHz, D₂O, ppm) δ 2.12-2.17 (m, 1H), 2.38 (s, 6H), 2.50-2.56(m, 1H), 3.25-3.27 (m, 2H), 3.36-3.39 (m, 2H), 3.53-3.55 (m, 1H),3.70-3.74 (m, 2H), 3.78-3.84 (m, 2H), 3.85 (s, 3H) 3.93 (s, 3H),4.04-4.08 (m, 4H), 5.71-5.75 (d, J=12 Hz, 1H), 6.18-6.24 (d, J=17.4 Hz,1H), 6.53-6.63 (m, 1H), 6.74 (s, 1H), 7.23-7.39 (m, 3H), 7.59-7.61 (d,J=7.8 Hz, 1H), 8.10-8.31 (m, 2H), 8.76 (s, 1H), 9.44 (s, 1H),10.10-10.12 (br s, 1H).

Example 27

1. Synthesis of Compound 27

The reaction steps and conditions of compound 27 and themethanesulfonate (MsOH)₃ of compound 27 were completely the same asthose from the first step to the third step in Example 8, except thatthe intermediate 008-1 as a raw material in the first step of theexample 8 was replaced with the intermediate 027-1 in the first step.LCMS C₃₂H₃₇N₇O₃: (ES, m/z): 568 [M+H]⁺. ¹H-NMR: (300 MHz, D₂O, ppm) δ1.84-1.98 (m, 2H), 2.26-2.22 (m, 2H), 2.76 (s, 9H), 2.80-2.84 (m, 2H),3.17-3.28 (m, 4H), 3.38 (s, 1H), 3.48-3.58 (m, 5H), 3.78-3.86 (m, 5H),4.12-4.16 (m, 2H), 5.86-5.89 (d, J=10.8 Hz, 1H), 6.22-6.27 (m, 1H),6.46-6.55 (m, 1H), 6.67-6.69 (d, J=6.9 Hz, 1H), 6.85 (s, 1H), 7.02 (brs, 1H), 7.17-7.22 (m, 2H), 7.40-7.43 (d, J=6.9 Hz, 1H), 7.60 (br s, 1H),7.879-7.99 (m, 2H).

Example 28

1. Synthesis of Intermediate 028-2

Under nitrogen protection, anhydrous N,N-dimethylformamide (DMF) (150mL) was added to a 250 mL single-necked flask and then the intermediate028-1 (375.5 mg, 3.05 mmol) was added thereto. The reaction mixture wascooled to 0° C. under an ice-water bath. After sodium hydride (NaH)(65%, mineral oil mixture) (564 mg, 15.2 mmol) was added the reactionmixture in batches, the reaction temperature was raised to roomtemperature and the reaction was carried out for 0.5 h. Then, theintermediate 006-5 (1.0 g, 2.54 mmol) was added into the reactionmixture, and the reaction was carried out at room temperature overnight.After the reaction was completed, the reaction was cooled to 0° C. andquenched by the adding 2 mL of MeOH and subjected to rotary evaporation.The crude product was purified by silica gel column chromatography(eluent: DCM/MeOH=8:1-6:1) and subjected to rotary evaporation to give0.8 g of the intermediate 028-2 (68%) as a yellow solid. LCMS: 461.2.

2. Synthesis of Compound 28

The two reaction steps and conditions of synthesizing compound 28 werecompletely the same as those of the second step in Example 8 and thefourth step in Example 22 respectively. LCMSLCMS (parent molecule)C₂₇H₂₈N₆O₃: (ES, m/z): 485 [M+H]⁺. ¹H-NMR (300 MHz, DMSO-D₆, ppm): δ2.32 (s, 3H), 3.07-3.11 (dd, J=6.9 Hz, J=13.2 Hz, 2H), 3.76-3.80 (dd,J=8.1 Hz, J=14.4 Hz, 2H), 3.84 (s, 3H), 3.88 (s, 3H), 4.83-4.87 (m, 2H),5.70-5.74 (d, J=12 Hz, 1H), 6.20-6.26 (d, J=16.8 Hz, 1H), 6.56 (s, 1H),6.65-6.76 (m, 1H), 7.12-7.26 (m, 2H), 7.49-7.52 (d, J=8.4 Hz, 1H), 7.88(s, 1H), 8.26-8.30 (m, 2H), 8.46 (s, 1H), 8.67 (s, 1H), 9.28 (s, 1H).

Example 29

1. Synthesis of Intermediate 029-2

The reaction step and condition of synthesizing compound 029-2 werecompletely the same as those the first step in Example 28, except thatanhydrous DMF in the first step of Example 28 as a solvent was replacedwith anhydrous tetrahydrofuran in this step. LCMS: 463.2.

2. Synthesis of Compound 29

The reaction steps and conditions of synthesizing compound 29 and themethanesulfonate (MsOH)₃ of compound 29 were the same as those of thesecond step and the third step in Example 8. LCMSLCMS (parent molecule)C₂₇H₃₀N₆O₃: (ES, m/z): [M+H]⁺=487. ¹H-NMR (300 MHz, DMSO-D₆, ppm) δ2.28-2.36 (m, 6H), 2.95-3.05 (m, 6H), 3.65-3.73 (m, 2H), 3.86 (s, 3H),3.93 (s, 3H), 4.51 (s, 2H), 5.75-5.78 (d, J=10.1 Hz, 1H), 6.21-6.27 (d,J=16.8 Hz, 1H), 6.62-6.71 (m, 1H), 7.01 (s, 1H), 7.19-7.22 (m, 1H),7.28-7.33 (t, J=7.8 Hz, 1H), 7.37-7.39 (d, J=6.3 Hz, 1H), 7.58-7.61 (d,J=8.4 Hz, 1H), 8.17-8.18 (br s, 1H), 8.33-8.76 (m, 2H), 9.41 (s, 1H),9.61 (br s, 1H).

Example 30

1. Synthesis of Intermediate 030-2

The reaction step and condition of synthesizing intermediate 030-2 werethe same as those of the first step in Example 28, except that anhydroustetrahydrofuran was used as a solvent in this step. LCMS: 505.2.

2. Synthesis of Compound 30

The reaction steps and conditions of synthesizing compound 30 and themethanesulfonate (MsOH)₃ of compound 30 were the same as those of thesecond step and the third step in Example 8. LCMSLCMS (parent molecule)C₂₉H₃₂N₈O₄: (ES, m/z): [M+H]⁺=529. ¹H-NMR (300 MHz, D₂O, ppm) δ 2.73 (s,6H), 3.23-3.60 (m, 9H), 3.80 (s, 3H), 3.91-4.25 (m, 4H), 4.36-4.38 (m,2H), 5.87-5.90 (d, J=10.5 Hz, 1H), 6.28-6.34 (d, J=16.8 Hz, 1H),6.45-6.51 (m, 2H), 6.67 (s, 1H), 6.90 (br s, 1H), 7.13 (s, 2H), 7.25 (brs, 1H), 7.48 (br s, 1H), 7.70 (br s, 2H).

Example 31

1. Synthesis of Intermediate 031-2

The reaction step and condition of synthesizing compound 030-2 were thesame as those the first step in Example 28, except that anhydroustetrahydrofuran was used as a solvent in this step. LCMS: 518.2.

2. Synthesis of Compound 31

The reaction steps and conditions of synthesizing compound 31 and themethanesulfonate (MsO)₁ of compound 31 were the same as those of thesecond step and the third step in Example 8. LCMSLCMS (parent molecule)C₃₀H₃₅N₇O₃: (ES, m/z): [M+H]⁺=542. ¹H-NMR (300 MHz, CD₃OD, ppm) δ 2.74(9H), 3.07 (s, 3H), 3.62-3.91 (m, 10H), 3.97 (s, 3H), 3.97 (s, 3H),5.83-5.86 (d, J=11.7 Hz, 11H), 6.37-6.43 (d, J=18.3 Hz, 1H), 6.68-6.73(m, 1H), 7.05 (s, 1H), 7.26-7.39 (m, 3), 7.53-7.56 (d, =8.1 Hz, 1H),7.95-7.97 (d, J=6.6 Hz, 1H), 8.14 (br s, 1H), 8.44 (br s, 1H), 8.54 (s,1H).

Example 32

1. Synthesis of Intermediate 032-2

The reaction step and condition of synthesizing compound 030-2 were thesame as those the first step in Example 28, except that anhydroustetrahydrofuran was used as a solvent in this step. LCMS: 450.2.

2. Synthesis of Compound 32

The reaction steps and conditions of synthesizing compound 32 and themethanesulfonate (MsOH)₃ of compound 32 were the same as those of thesecond step and the third step in Example 8. LCMSLCMS (parent molecule)C₂₆H₂₇N₅O₄: (ES, m/z): [M+H]⁺=474. ¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 2.27(s, 3H), 3.37 (s, 3H), 3.75-3.78 (dd, J=4.8 Hz, J=9.3 Hz, 2H), 3.83-3.88(s, 3H), 3.98 (s, 3H), 4.30-4.33 (dd, J=4.5 Hz, J=9.3 Hz, 2H), 5.70-5.73(d, J=9.9 Hz, 1H), 6.17-6.22 (d, J=17.1 Hz, 1H), 6.61-6.70 (m, 1H), 7.00(s, 1H), 7.20-7.39 (m, 3H), 7.59-7.61 (d, J=8.1 Hz, 1H), 8.16-8.27 (brs, 3H), 8.77 (s, 1H), 9.29 (s, 1H).

Example 33

1. Synthesis of Intermediate 052-1

The reaction steps and conditions of synthesizing compound 33 and themethanesulfonate (MsOH)₃ of compound 33 were the same as those of thefourth step and the sixth step in Example 6, except that theintermediate 006-6 as a raw material in the fourth step of the example 6was replaced with the intermediate 033-1 in this step. LCMS (parentmolecule) C₂₉H₃₄N₆O₄: (ES, m/z): [M+H]⁺=531.

¹H-NMR (300 MHz, D₂O, ppm) δ 3.07-3.20 (m, 4H), 3.24 (m, 8H), 3.31-3.40(m, 5H), 3.73-3.77 (m, 3H), 5.71-5.74 (m, 1H), 5.90-6.01 (m, 1H),6.23-6.32 (m, 2H), 6.70-6.87 (m, 2H), 6.93-6.95 (d, J=7.2 Hz, 1H),7.05-7.08 (m, 1H), 7.12-7.20 (d, J=22.8 Hz, 2H), 7.74-7.87 (m, 1H),8.09-8.17 (m, 1H).

Example 34

1. Synthesis of Compound 34

The reaction steps and conditions of synthesizing compound 34 and themethanesulfonate (MsOH)₃ of compound 34 were the same as those from thefirst step to the third step in Example 8, except that the intermediate008-1 as a raw material in the first step of the example 8 was replacedwith the intermediate 034-1 in the this step. LCMS (parent molecule)C₃₀H₃₅N₇O₂: (ES, m/z): [M+H]⁺=526. ¹H-NMR (300 MHz, DMSO-D₆, ppm) δ1.82-1.86 (m, 3H), 2.09 (s, 1H), 2.73 (s, 9H), 2.85-2.91 (d, J=15.6 Hz,8H), 3.08-3.14 (m, 1H), 3.29-3.33 (m, 1H), 3.52 (s, 4H), 3.82 (s, 3H),5.88-5.91 (d, J=10.5 Hz, 1H), 6.26-6.31 (d, J=17.4 Hz, 1H), 6.54-6.63(m, 1H), 6.71-6.74 (d, J=7.2 Hz, 1H), 6.91 (s, 1H), 7.00-7.05 (m, 1H),7.19-7.45 (m, 2H), 7.46 (d, J=6.9 Hz, 1H), 7.65 (s, 1H), 7.89-7.93 (m,2H).

Example 35

1. Synthesis of Intermediate 035-2

The intermediate 001-5 (3 g, 0.02 mol), 30 mL of n-butanol, theintermediate 035-1 (1.8 g, 0.013 mol) and DIPEA (3.35 g, 0.026 mol) wereadded into a 100 mL single-necked flask sequentially, and then thereaction was heated to 105° C. and maintained for 2.5 h. The reactionwas cooled to room temperature, and the reaction mixture was subjectedto rotary evaporation, and the crude product was purified through silicagel column chromatography (eluent: EA:PE=1:15) to give 1.6 g of theintermediate 035-2 (48%) as a white solid. LCMS: 246.1.

2. Synthesis of Intermediate 035-3

The reaction step and condition of synthesizing the intermediate 035-3were the same as those of the third step in Example 6, except that theintermediate 006-2 in the example 6 was replaced with the intermediate035-2 as a starting material in the this step. LCMS: 396.1.

3. Synthesis of Compound 35

The reaction steps and conditions of synthesizing compound 35 and themethanesulfonate (MsOH)₃ of compound 35 were the same as those from thefirst step to the third step in Example 7, except that the intermediate006-5 in the first step of the example 7 was replaced with theintermediate 035-3 in the this step and the intermediate 007-1 as a rawmaterial in the first step of the example 7 was replaced with theintermediate 001-10 in the this step. The analysis data of themethanesulfonate (MsOH)₃ of compound 35: LCMS (parent molecule)C₂H₃₅N₇O₂: (ES, m/z): [M+H]⁺=502.

¹H-NMR (300 MHz, D₂O, ppm) δ 1.75-1.90 (m, 2H), 2.46-2.51 (m, 2H),2.69-2.76 (m, 18H), 3.19 (m, 2H), 3.42-3.46 (m, 2H), 3.68 (m, 2H), 3.83(m, 2H), 5.86-5.89 (d, J=10.5 Hz, 1H), 6.23-6.29 (m, 1H), 6.51-6.54 (m,2H), 6.97-7.11 (m, 5H), 7.5-8.2 (m, 2H).

Example 36

1. Synthesis of Intermediate 036-2

The reaction step and condition of synthesizing the intermediate 036-2were the same as those of the first step in Example 35. LCMS: 248.1.

2. Synthesis of Intermediate 036-3

The reaction step and condition of synthesizing the intermediate 036-3were the same as those of the third step in Example 6, except that theintermediate 006-2 in the example 6 was replaced with the intermediate036-2 as a starting material in the this step. LCMS: 398.1.

3. Synthesis of Compound 036

The reaction steps and conditions of synthesizing compound 36 and themethanesulfonate (MsOH)₃ of compound 36 from the intermediate 036-3 werethe same as those from the first step to the third step in Example 7,except that the intermediate 006-5 in the first step of the example 7was replaced with the intermediate 036-3 in the this step and theintermediate 007-1 as a raw material in the first step of the example 7was replaced with the intermediate 001-10 in the this step. The analysisdata of the methanesulfonate (MsOH)₃ of compound 36:

LCMS (parent molecule) C₂₇H₃₃N₇O₃: (ES, m/z): [M+H]⁺=504 [M+1]⁺.

¹H-NMR (300 MHz, D₂O, ppm) δ 2.63 (s, 3H), 2.70 (s, 12H), 2.78 (s, 3H),3.21 (m, 2H), 3.40-3.36 (m, 2H), 3.80 (s, 3H), 3.96 (m, 2H), 4.17 (m,2H), 5.84-5.87 (d, J=10.8 Hz, 1H), 6.22-6.27 (m, 1H), 6.41-6.50 (m, 1H),6.82-6.93 (m, 4H), 7.06 (br s, 1H), 7.73-7.85 (m, 2H).

Example 37

1. Synthesis of Intermediate 037-2

The intermediate 001-5 (2.22 g, 14.9 mmol), anhydrous THE (25 mL), 037-1(1.5 g, 10.2 mmol) and DIPEA (2.58 g, 20.0 mmol) were added into a 100mL single-necked flask sequentially, and then the reaction was heated to75° C. and maintained under stirring for 2.5 h. The reaction was cooledto room temperature, and the reaction mixture was subjected to rotaryevaporation, and the crude product was purified through silica gelcolumn chromatography (eluent: EA:PE=1:15) to give 1.5 g of theintermediate 037-2 (57%) as a white solid. LCMS: 260.1.

2. Synthesis of Intermediate 037-3

3. Synthesis of Compound 37

The reaction steps and conditions of synthesizing compound 37 and themethanesulfonate (MsOH)₃ of compound 37 from the intermediate 037-3 werethe same as those from the third step to the fifth step in Example 3,except that the intermediate 003-3 in the third step of the example 3was replaced with the intermediate 037-3 in the this step. The analysisdata of the methanesulfonate (MsOH)₃ of compound 37: LCMS (parentmolecule) C₂₉H₃₇N₇O₂: (ES, m/z): [M+H]⁺=516. ¹H-NMR (300 MHz, D₂O, ppm)δ 1.03-1.12 (s, 6H), 2.70-2.79 (m, 18H), 3.24-3.26 (m, 2H), 3.43 (m,2H), 3.65 (m, 2H), 3.79 (s, 3H), 5.78-5.82 (d, J=10.5 Hz, 1H), 6.16-6.22(m, 2H), 6.38-6.44 (m, 1H), 6.75 (m, 1H), 6.93-7.00 (m, 2H), 7.11-7.13(m, 1H), 7.61-7.78 (m, 3H).

Example 38

1. Synthesis of Intermediate 038-2

The intermediate 038-1 (3 g, 13.4 mmol) as the raw material wasdissolved in 30 mL of anhydrous acetonitrile in a 100 mL three-neckedflask at room temperature under a nitrogen atmosphere, followed by theaddition of anhydrous potassium carbonate (5.57 g, 40.0 mmol). Thetemperature was raised to 60° C. overnight. The next day, the reactionsystem was cooled to room temperature. The mixture was filtered and thefilter cake was washed once with 10 mL of anhydrous ethanol. Thefiltrate was collected and the filtrate temperature was reduced to 0° C.Sodium borohydride (511 mg, 13.9 mmol) was added in batches, and thenheated up to room temperature and the reaction was carried out for 2 h.After the reaction was completed, the reaction was quenched by adding 1mL of water and the reaction mixture was concentrated. The crude productwas purified through silica gel column chromatography (eluent:EA/PE=1:10-1:3) to give 1.45 g of the intermediate 038-2 (75%) as ayellow oil. LCMS: 146.1.

2. Synthesis of Intermediate 038-4

The intermediate 038-3 (1.45 g, 9.99 mmol) as raw material was dissolvedin 30 mL of anhydrous acetonitrile in a 100 mL three-necked flask atroom temperature under a nitrogen atmosphere, followed by addinganhydrous potassium carbonate (4.14 g, 29.7 mmol) and2,4-dichloropyrimidine (1.48 g, 9.93 mmol). The temperature was raisedto 60° C. overnight and the reaction was stirred overnight. The nextday, the reaction was completed, followed by that the reaction systemwas cooled to room temperature, diluted with 100 mL of water andextracted with 100 mL of methylene chloride 3 times. The organic phaseswere combined, backwashed with 100 mL of saturated brine 3 times, driedover anhydrous sodium sulfate, and then concentrated. The crude productwas purified through silica gel column chromatography (EA/PE=1:10-1:3)to give 0.9 g of the intermediate 038-4 (35%) as a white solid. LCMS:258.1.

3. Synthesis of Intermediate 038-6

The reaction step and condition of synthesizing the intermediate 038-6were the same as those of the sixth step and the seventh step inExample 1. LCMS: 490.2

4. Synthesis of Intermediate 038-7

The intermediate 038-6 (700 mg, 1.43 mmol) as a raw material wasdissolved in 30 mL of anhydrous ethanol and 10 mL water in a 100 mLsingle-necked flask at room temperature, and iron powder (481 mg, 8.61mmol) and ammonium chloride (53 mg, 0.99 mmol) were added into thereaction system sequentially. Then, the reaction was heated to 85° C.and carried out overnight. After the reaction was completed, thereaction system was cooled to room temperature. The reaction mixture wasfiltered, and the filtrate was collected concentrated to dryness. Theresidue was purified by Prep-HPLC (column: C18 silica gel; flow phase:acetonitrile/water (0.05% trifluoroacetic acid); 30% acetonitrile to 50%acetonitrile; 5 min; detection wavelength: 254 nm) to give 600 mg of theintermediate 038-7 (73%) as a white solid. LCMS: 460.3.

5. Synthesis of Compound 38

The reaction steps and conditions of synthesizing compound 38 and thehydrochloride (HCl) of compound 38 from the intermediate 038-7 were thesame as those of the ninth step in Example 1. The analysis data of thehydrochloride (HCl) of compound 38: LCMS (parent molecule) C₂₉H₃₅N₇O₂:(ES, m/z): 514 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ 1.09-1.21 (m,4H), 2.66 (s, 3H), 2.74 (s, 3H), 2.76 (s, 3H), 3.27-3.35 (m, 4H), 3.83(s, 3H), 4.23 (s, 2H), 5.67-5.71 (m, 1H), 6.16-6.22 (m, 1H), 6.87-6.88(m, 1H), 7.02 (m, 3H), 7.14-7.22 (m, 1H), 8.03-8.17 (m, 2H), 9.94 (br s,1H), 10.60 (br s, 1H).

Example 39

1. Synthesis of Intermediate 039-2

The intermediate 001-5 (8.8 g, 59.1 mmol), the intermediate 039-1 (7.06g, 65.4 mmol), n-butanol (70 mL) and DIPEA (15.4 g, 119.2 mmol) weresequentially added in a 250 ML single-necked flask under a nitrogenatmosphere. The reaction was raised to 110° C. and stirred overnight.The reaction system was cooled to room temperature and then the reactionsystem was subjected to rotary evaporation. A solution of 0.1 Mhydrochloric acid (HCl) (300 mL) was added and a solid was precipitated.The reaction mixture was filtered, the filter cake was collected andwashed three times with anhydrous ether (100 mL). The filter cake wasdried to give 5.0 g of crude product 039-2 (38%) as a white solid. LCMS.221.1.

2. Synthesis of Intermediate 039-4

The intermediate 039-2 (5.0 g, 22.7 mmol), 100 mL of anhydrous THF,carbonyldiimidazole (CDI) (039-3) (7.37 g, 45.5 mmol) and pyridine (3.59g, 45.4 mmol) were sequentially added in a 250 mL three-necked flaskunder a nitrogen atmosphere, followed by that the reaction system washeated to 64° C. and stirred for 2 h. The reaction was cooled to roomtemperature and quenched with 500 mL of ice water to precipitate asolid. The mixture was filtered to collect the filter cake which wasdried to give 4.1 g of crude product 039-4 (73%) as a white solidproduct. LCMS: 247.0.

3. Synthesis of Intermediate 039-6

The reaction step and condition of synthesizing intermediate 039-6 werethe same as those of the sixth and seventh steps in Example 1. LCMS:479.2

4. Synthesis of Intermediate 039-7

The reaction step and condition of synthesizing intermediate 039-7 werethe same as those of the fourth step in Example 38. LCMS: 449.2.

5. Synthesis of Compound 39

The reaction steps and conditions of synthesizing compound 39 and themethanesulfonate (MsOH)₃ of compound 39 from the intermediate 038-7 werethe same as those of the ninth step in Example 1. The analysis data ofthe methanesulfonate (MsOH)₃ of compound 39: LCMS (parent molecule)C₂₆H₃N₈O₃: (ES, m/z): [M+H]⁺=503. ¹H-NMR (300 MHz, D₂O, ppm) δ 2.66 (s,3H), 2.71 (s, 9H), 2.81 (s, 6H), 3.27-3.38 (m, 4H), 3.74 (s, 3H),5.82-5.85 (d, J=10.5 Hz, 1H), 6.22-6.28 (d, J=17.1 Hz, 1H), 6.44-6.53(m, 1H), 6.64-6.67 (m, 1H), 6.87-7.02 (m, 3H), 7.45 (m, 1H), 7.66-7.74(m, 2H), 8.03-8.06 (m, 1H).

Example 40

1. Synthesis of Intermediate 040-1

The intermediate 039-4 (1.5 g, 6.08 mmol) and anhydrousN,N-dimethylformamide (DMF) (30 mL) were sequentially added in a 100 mLthree-necked flask under a nitrogen atmosphere, followed by cooling thereaction system to 0° C. Sodium hydride (NaH) (220 mg, 9.17 mmol) wasadded in batches for 10 min. The reaction system was incubated at 0° C.for 1 h. In the condition of darkness, the reaction was carried out byadding methyl iodide (1.37 g, 9.65 mmol) for 4h, and then quenched byadding 400 mL of ice water and a solid was precipitated. The reactionmixture was filtered, the filter cake was collected and dried to give1.5 g of crude product 040-1 (95%) as a white solid.

2. Synthesis of Intermediate 040-2

The intermediate 040-1 (1.5 g, 5.75 mmol), intermediate 006-4 (1.07 g,5.76 mmol), isopropanol (30 mL) and p-toluenesulfonic acid (1.19 g, 6.92mmol) were sequentially added into a 100 mL of single-necked flask undera nitrogen atmosphere, followed by heating the reaction system to 105°C. and stirred overnight. The reaction was cooled to room temperature.The reaction mixture was filtered to collect the filter cake which waswashed with 50 mL of isopropanol three times and washed with 100 mL ofacetonitrile three times, and dried to give 1.3 g of crude product 040-2(55%) as a yellow solid. LCMS: 411.1.

3. Synthesis of Intermediate 040-3

Anhydrous NMP (20 mL), the intermediate 040-2 (1.3 g, 3.17 mmol), theintermediate 001-10 (485 mg, 4.75 mmol) and anhydrous K₂C₀₃ (1.31 g,9.43 mmol) were sequentially added in a 100 mL single-necked flask undera nitrogen atmosphere, followed by heating the reaction system to 100°C. and stirred for 5h. Then, the reaction system was cooled to a roomtemperature, and quenched by adding 500 mL of ice water. The reactionmixture was filtered, the filter cake was collected, washed with 50 mLof ether three times and dried to give 1.2 g of crude product 040-3(77%) as a red solid.

LCMS: 493.2.

4. Synthesis of Intermediate 040-4

Anhydrous ethanol (180 mL), water (60 mL), the intermediate 040-3 (1.2g, 2.44 mmol), iron powder (Fe) (820 mg, 14.7 mmol) and ammoniumchloride (91 mg, 1.70 mmol) were sequentially added into a 500 mL ofsingle-necked flask under a nitrogen atmosphere, followed by heating thereaction system to 85° C. and stirred overnight. The reaction mixturewas filtered, and the filtrate was concentrated to dryness. The crudeproduct was purified by high pressure liquid chromatography (Prep-HPLC)(column type: Waters X-bridge RP18, 19×150 mm, 5 um; mobile phase:acetonitrile/water (0.05% TFA), 33% acetonitrile to 37% acetonitrile, 5min, flow rate: 20 mL/min; detection wavelength: 254 nm). The collectedproduct was concentrated to dryness to give 0.7 g of crude product 040-4(62%) as a gray solid. LCMS: 463.2.

5. Synthesis of Compound 40

The intermediate 040-4 (300 mg, 0.65 mmol), anhydrous THE (20 mL) andDIPEA (167.6 mg, 1.30 mmol) were sequentially added into a 50 mL ofthree-necked flask under a nitrogen atmosphere, followed by cooling thereaction system to 0° C. and the intermediate 001-13 (53 mg, 0.59 mmol)was added thereto. The reaction mixture was incubated for 1 h at 0° C.and then subjected to rotary evaporation. The crude product was purifiedby high pressure liquid chromatography (Prep-HPLC) (column type: WatersX-bridge RP18, 19×150 mm, 5 um; mobile phase: water (0.05% aqueousammonia)/acetonitrile, 50% acetonitrile to 55% acetonitrile, 5 min, flowrate: 20 mL/min; detection wavelength: 254 nm), collected, andconcentrated to dryness to give 120 mg of product 40.

120 mg of the product was dissolved in 50 mL of acetonitrile, 67 mg ofmethanesulfonic acid was added and stirred at room temperature for 1 h.The reaction mixture was filtered, and the filter cake was collected anddried to give 0.156 g of methanesulfonate (MsOH)₃ of compound 40 (30%)as a yellow solid. LCMS (parent molecule) C₂₇H₃₂N₈O₃: (ES, m/z):[M+H]⁺=517. ¹H-NMR (300 MHz, D2O, ppm) δ 2.66 (s, 3H), 2.71 (s, 9H),2.82 (s, 6H), 3.04 (s, 3H), 3.29-3.38 (m, 4H), 3.78 (s, 3H), 5.83-5.86(d, J=10.8 Hz, 1H), 6.24-6.30 (d, J=16.8 Hz, 1H), 6.46-6.61 (m, 2H),6.80-6.82 (m, 1H), 6.96-6.99 (m, 2H), 7.45 (m, 1H), 7.63-7.70 (m, 2H),8.03 (d, J=6.3 Hz, 1H).

Example 41

1. Synthesis of Intermediate 041-2

The intermediate 001-5 (2.0 g, 13.4 mmol) was dissolved in DME (100 mL)in a 250 mL of three-necked flask under a nitrogen atmosphere, followedby addition of the intermediate 041-1 (2.96 g, 12.2 mmol),tetrakis(triphenylphosphine)palladium (1.0 g, 2.68 mmol) and sodiumbicarbonate (40 mL, 1.0 M of aqueous solution). The reaction system washeated to reflux for 3 hours under nitrogen. After the reaction wascompleted, the reaction was quenched by adding 100 mL of ice water. Thereaction system was extracted with 200 mL of ethyl acetate twice. Theorganic phases were combined, washed twice with 100 mL of saturatedbrine and purified by silica gel column chromatography (100-200 meshsilica gel, eluent: PE:EA=100:1) to give 1.9 g of product 041-2 (62%) asa yellow solid. LCMS: 230.0

2. Synthesis of Intermediate 041-3

The intermediate 041-2 (1.9 g, 8.29 mmol) was dissolved in 50 mL ofanhydrous tetrahydrofuran. Maintaining the reaction temperature at 0-10°C., sodium hydride (NaH) (dispersed in mineral oil at a content of 60%)(829 mg, 20.7) was added in batches, then stirring for 30 min at 0° C.Iodomethane (Mel) (1.4 g, 10.3 mmol) was added to the reaction systemand then the reaction temperature was heated up to room temperature. Thereaction was continued for 2 hours. After the reaction was completed, 20mL of ice water was added to quench the reaction. The reaction mixturewas extracted with 50 mL of ethyl acetate twice. The organic phases werecombined, washed twice with 50 mL of saturated brine, dried overanhydrous sodium sulfate and concentrated to dryness, so as to give 1.1g of crude product 041-3 (55%) as a yellow solid. LCMS: 244.1.

3. Synthesis of Compound 41

The reaction steps and conditions of synthesizing the hydrochloride(HCl)_(n) of compound 41 from the intermediate 041-3 were the same asthose of the sixth to the ninth steps in Example 1. The analysis data ofthe hydrochloride (HCl) of compound 41: LCMS (parent molecule)C₂₈H₃₃N₇O₂: (ES, m/z): [M+H]⁺=500. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ2.64 (s, 3H), 2.74-2.76 (d, J=4.8 Hz, 6H), 3.23-3.32 (m, 4H), 3.71-3.85(m, 3H), 3.87-3.91 (d, J=14.1 Hz, 3H), 5.68-5.73 (m, 1H), 6.23-6.30 (m,1H), 6.98 (s, 1H), 7.06-7.13 (m, 2H), 7.27-7.33 (m, 1H), 7.47-7.53 (m,2H), 7.70 (t, J=7.8 Hz, 1H), 7.89 (t, J=7.5 Hz, 1H), 8.45-8.49 (m, 2H),9.82 (s, 1H), 10.34-10.37 (m, 1H).

Example 42

1. Synthesis of Intermediate 042-2

The reaction steps and conditions of synthesizing the intermediate 042-2were the same as those of the first step in Example 41. LCMS: 245.1.

2. Synthesis of Compound 42

The reaction steps and conditions of synthesizing the compound 42 andhydrochloride (HCl) of compound 42 from the intermediate 042-2 were thesame as those of the third to the fifth steps in Example 38. Theanalysis data of the hydrochloride (HCl) of compound 42: LCMS (parentmolecule) C₂₇H₃₂N₈O₂: (ES, m/z): [M+H]⁺=501. ¹H-NMR (300 MHz, DMSO-D₆,ppm) δ 2.66 (s, 3H), 2.76 (s, 3H), 2.78 (s, 3H), 3.30-3.38 (m, 4H), 3.80(s, 3H), 4.08 (s, 3H), 5.67-5.70 (m, 1H), 6.12-6.25 (m, 1H), 7.05 (s,1H), 7.25-7.34 (m, 1H), 7.54-7.59 (m, 1H), 7.75-7.77 (d, J=6.3 Hz, 1H),7.95-7.96 (d, J=8.4 Hz, 1H), 8.12-8.15 (d, J=7.5 Hz, 1H), 8.29 (s, 1H),8.39 (br s, 1H), 8.50-8.52 (m, 1H), 9.90 (s, 1H), 10.15 (br s, 1H),10.86 (br s, 1H).

Example 43

1. Synthesis of Intermediate 043-3

Aluminum trichloride (5.9 g, 69.5 mmol) was dissolved in methylenedichloride (DCM) (134 mL) at room temperature in a 1000 mL ofthree-necked flask under nitrogen atmosphere, followed by sequentiallyadding the intermediate 043-2 (4.9 mL) and boron trichloride (BCl₃) (40mL, 1 M of dichloromethane solution). The reaction was carried out atroom temperature for 0.5 h, and then the intermediate 006-1 (5 g, 38.1mmol) added. Next, the reaction was continued at room temperature for2h. Then, the reaction mixture was cooled to 0° C., and dropping asolution of intermediate 043-1 (9.36 g, 83.0 mmol) dissolved in 84.2 mLof pure triethylamine (NEt₃, or TEA), then the reaction was continued atroom temperature for 2h. After the reaction was completed, 200 mL of icewater was added to quench the reaction. The mixture was extracted threetimes with 200 mL of dichloromethane. The organic phases were combinedand washed three times with 100 mL of saturated brine. The organicphases were dried with anhydrous sodium sulfate, concentrated todryness. The crude product was purified by silica gel columnchromatography (EA/PE=1:50-1:20) to give 7 g of product 043-3 (71%) asbrown oil. LCMS: 258.0.

2. Synthesis of Intermediate 043-5

The intermediate 043-4 (0.19 g, 6.18 mmol) was dissolved in 5 mL oftoluene and 2.5 mL of water at room temperature in 100 mL of athree-necked flask under nitrogen atmosphere, followed by sequentiallyadding the intermediate 043-3 (1.6 g, 6.22 mmol), Pd(PhP₃)₄ (245 mg,0.31 mmol), potassium phosphate (K₃PO₄) (3.96 g, 18.7 mmol). Thereaction was heated to 95° C. overnight. After the reaction wascompleted, the reaction mixture was cooled to room temperature. Thereaction was quenched by adding 100 mL of ice water into the reactionmixture. The obtained mixture was extracted with 100 mL ofdichloromethane three times. The organic phases were combined and washedwith 300 mL of saturated brine three times. The organic phases weredried over anhydrous sodium sulfate and concentrated to dryness. Theproduct was purified by silica gel column chromatography(EA/PE=1:10-1:3) to give 0.7 g of product 043-5 (47%) as a green solid.LCMS: 243.0.

3. Synthesis of Intermediate 043-6

The intermediate 043-5 (0.19 g, 6.18 mmol) as a raw material wasdissolved in 1,4-dioxane (10 mL) at room temperature in 100 mL of athree-necked flask under nitrogen atmosphere, followed by sequentiallyaddition of the intermediate 006-4 (538 mg, 2.89 mmol),4,5-bisdiphenylphosphine-9,9-dimethyoxyanthene (xantphos) (167 mg, 0.29mmol), cesium carbonate (Cs₂CO₃) (1.89 g, 5.77 mmol) and palladiumacetate (Pd(OAc)₂) (32.4 mg, 0.14 mmol) into the reaction system. Afterheated to 100° C., the reaction was carried out for 5h. After thereaction was completed, the reaction mixture was cooled to roomtemperature. The reaction was quenched by adding 100 mL of ice waterinto the reaction mixture. The obtained mixture was extracted with 100mL of dichloromethane three times. The organic phases were combined andwashed with 300 mL of saturated brine three times. The organic phaseswere dried over anhydrous sodium sulfate and concentrated to dryness togive 0.4 g of product 043-6 (36%) as yellow oil. LCMS: 389.0.

4. Synthesis of Intermediate 043-8

The reaction steps and conditions of synthesizing the intermediate 043-8from the intermediate 043-6 were the same as those of the third and thefourth steps in Example 40. LCMS: 445.0.

5. Synthesis of Compound 43

The reaction steps and conditions of synthesizing the compound 43 andhydrochloride (HCl) of compound 43 from the intermediate 043-8 were thesame as those of the ninth step in Example 1. The analysis data of thehydrochloride (HCl)_(n) of compound 43: LCMS (parent molecule)C₂₉H₃₄N₆O₂: (ES, m/z): [M+H]⁺=499. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ10.68 (br s, 1H), 10.22 (s, 1H), 9.95 (s, 1H), 8.41 (s, 1H), 8.09 (s,1H), 8.00-8.02 (d, J=7.8 Hz, 1H), 7.84-7.86 (d, J=6.9 Hz, 1H), 7.63-7.55(d, J=7.5 Hz, 1H), 7.55 (s, 1H), 7.22-7.38 (m, 4H), 7.04 (s, 1H),6.22-6.28 (m, 1H), 5.70-5.74 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.36(m, 4H), 2.75 (s, 3H), 2.73 (s, 3H), δ 2.65 (s, 3H).

Example 44

1. Synthesis of Intermediate 044-3

The reaction step and condition of synthesizing intermediate 044-3 werethe same as those of the first step in Example 6. LCMS: 244.1.

2. Synthesis of Intermediate 044-6

The reaction step and condition of synthesizing the intermediate 044-6from the intermediate 044-3 were the same as those of the third and thefourth steps in Example 38. LCMS: 446.3.

3. Synthesis of Compound 44

The reaction steps and conditions of synthesizing the compound 44 andhydrochloride (HCl)_(n) of compound 44 from the intermediate 044-6 werethe same as those of the ninth step in Example 1. The analysis data ofthe hydrochloride (HCl)_(n) of compound 44: LCMS (parent molecule)C₂₈H₃₃N₇O₂: (ES, m/z): [M+H]⁺=500. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ2.51 (s, 3H), 2.73 (s, 3H), 2.75 (s, 3H), 3.32-3.36 (m, 4H), 3.91 (s,3H), 3.95 (s, 3H), 5.70-5.74 (m, 1H), 6.21-6.28 (m, 1H), 7.00 (s, 1H),7.12-7.21 (m, 1H), 7.35-7.52 (m, 2H), 7.68-7.70 (d, J=8.1 Hz, 1H),8.05-8.06 (m, 1H), 8.30-8.41 (m, 1H), 8.45 (s, 1H), 8.75 (s, 1H), 9.93(s, 1H), 10.49-10.51 (m, 2H).

Example 45

1. Synthesis of Intermediate 045-1

The intermediate 006-5 (1.0 g, 2.54 mmol) as a raw material wasdissolved in NMP (20 mL) in 50 mL of a single-necked flask at roomtemperature, followed by sequentially addition of the intermediate001-10 (250 mg, 2.45 mmol) and K₂CO₃ (1.04 g, 7.38 mmol) into thereaction system. After heated to 105° C., the reaction was carried outwith a stirring for 2h. After the reaction was completed, the reactionmixture was cooled to room temperature. The reaction was quenched byadding 50 mL of ice water into the reaction mixture. The obtainedmixture was filtered by suction and the filter cake was collected andthen dissolved in 200 mL of dichloromethane. The organic phases werewashed with 100 mL of saturated brine once, dried over anhydrous sodiumsulfate and concentrated to dryness. The crude product was purified bysilica gel column chromatography (dichloromethane/methanol=100/1-50/1)to give 805 mg of the intermediate 045-1 (67%) as a red solid. LCMS:476.2.

2. Synthesis of Intermediate 045-2

The reaction step and condition of synthesizing the intermediate 045-2from the intermediate 045-1 were the same as those of the eighth step inExample 1. LCMS: 446.3.

3. Synthesis of Compound 45

Under a nitrogen atmosphere, the intermediate 045-2 (350 mg, 0.79 mmol)as a raw material was dissolved in dichloromethane (50 mL) at roomtemperature in a 100 mL three-necked flask, followed by adding DIPEA(202 mg, 1.56 mmol). The reaction system was cooled to 0° C. Ethylenesulfonyl chloride (99 mg, 0.78 mmol) was added dropwisely to thereaction system at 0° C., and then the reaction was continued for 30minutes at 0° C. After the reaction was completed, the mixture wasconcentrated to dryness. The crude product was purified by silica gelcolumn chromatography (dichloromethane/methanol=100:1-50:1), collected,and concentrated to give product 45.

The product 45 was added and dissolved in 3 mL of aqueous hydrochloricacid (2 M), the reaction was stirred at room temperature for 30 minutesand then freeze dried to give 47.8 mg of the hydrochloride (HCl) ofcompound 45 (10%) as a yellow solid. LCMS (parent molecule) C₂₇H₃₃N₇O₃S:(ES, m/z): [M+H]⁺=536. ¹H-NMR: (DMSO-D₆, 300 MHz, ppm) δ 10.30-10.23 (m,1H), 8.77 (s, 1H), 8.21-8.16 (m, 2H), 7.62-7.59 (m, 2H), 7.42-7.40 (d,J=6 Hz, 1H), 7.35-7.30 (m, 1H), 7.23-7.17 (m, 1H), 7.05 (s, 1H),6.93-6.84 (m, 1H), 6.12-6.09 (d, J=9 Hz, 1H), 5.96-5.93 (d, J=9 Hz, 1H),3.92 (s, 3H), 3.80 (s, 3H), 3.38-3.35 (m, 4H), 2.79 (s, 6H), 2.63 (s,3H).

Example 46

1. Synthesis of Compound 46

The reaction step and condition of synthesizing the compound 46 from theintermediate 012-3 were the same as those of the third step in Example45.

The obtained product 46 was dissolved in 5 mL of acetonitrile,methanesulfonic acid (115.3 mg, 1.20 mmol) was added thereto. Then, thereaction was stirred for 2 h and then freeze dried to give 108.5 mg ofmethanesulfonate (MsOH)₂ of compound 46 (23%) as a yellow solid. LCMS(parent molecule) C₂₉H₃₅N₇O₃S: (ES, m/z): [M+H]⁺=562. ¹H-NMR: (DMSO-D₆,300 MHz, ppm) δ 8.69 (s, 1H), 8.29-8.19 (m, 1H), 7.61-7.58 (d, J=9 Hz,1H), 7.40-7.30 (m, 2H), 7.25-7.18 (m, 1H), 7.05 (s, 1H), 6.90-6.82 (m,1H), 6.18-6.12 (d, J=12 Hz, 1H), 6.01-5.98 (d, J=6 Hz, 1H), 3.98 (s,3H), 3.89 (s, 3H), 3.81-3.32 (m, 6H), 3.18-3.10 (m, 2H), 2.72 (s, 3H),2.33 (s, 6H), 2.27-1.98 (m, 4H).

Example 47

1. Synthesis of Intermediate 047-3

The reaction step and condition of synthesizing the intermediate 047-3from the intermediates 006-5 and 047-1 were the same as those of thefirst and second steps in Example 7. LCMS: 460.3.

2. Synthesis of Compound 47

The reaction steps and conditions of synthesizing the compound 47 andmethanesulfonate (MsOH)₂ of compound 47 from the intermediate 047-3 werethe same as those of the third step in Example 7. LCMS (parent molecule)C₂₉H₃₅N₇O₂: (ES, m/z): [M+H]⁺=514. ¹H-NMR: (DMSO-D₆, 300 MHz, ppm) δ9.25 (m, 2H), 8.77 (s, 1H), 8.39-8.24 (m, 2H), 7.60-7.58 (d, J=6 Hz,1H), 7.40-7.38 (d, J=6 Hz, 1H), 7.33-7.28 (m, 1H), 7.21-7.17 (m, 1H),7.02 (s, 1H), 6.75-6.66 (m, 1H), 6.27-6.20 (d, J=9 Hz, 1H), 5.77-5.74(d, J=9 Hz, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.14-3.11 (m, 2H),3.09-3.07 (m, 2H), 2.97 (s, 9H), 2.32 (s, 6H), 1.88-1.83 (m, 2H).

Example 48

1. Synthesis of Intermediate 048-2

The intermediate 048-1 (3.0 g, 25.6 mmol) as a raw material wasdissolved in 50 mL of 1,2-dichloroethane (DCE) in 100 mL of athree-necked flask at room temperature under a nitrogen atmosphere. Thereaction mixture was cooled to 0° C. Ethylmagnesium bromide (8.5 mL,25.6 mmol) was added dropwisely to the reaction system. After thereaction was completed, the reaction was maintained at a constanttemperature for 30 min and the intermediate 001-5 (5.4 g, 36.3 mmol) wasadded into the reaction system at 0° C. The reaction was carried outovernight at room temperature. After the reaction was completed, thereaction mixture was quenched by adding 100 mL of ice water. The mixturewas extracted with 100 mL of methylene dichloride three times. Theorganic phases were combined, washed with 100 mL of saturated brinethree times, dried over anhydrous sodium sulfate and concentrated. Thecrude product was purified by silica gel column chromatography(EA/PE=1:10-1:5) to give 2.0 g of the intermediate 048-2 (34%) as ayellow solid. LCMS: 229.0.

2. Synthesis of Intermediate 048-3

The intermediate 048-2 (80 mL) (2.0 g, 8.7 mmol) was dissolved inanhydrous tetrahydrofuran (80 mL) in a 50 mL of three-necked flask undernitrogen, and then the reaction mixture was cooled to 0-10° C. After NaH(60%, dispersed in a mineral oil) (200 mg, 8.33 mmol) was sequentiallyadded, the reaction system was stirred for 30 min at 0° C. and theniodoethane (1.6 g, 10.3 mmol) was added thereto. The reaction mixturewas heated to a room temperature and maintained for 2h. After thereaction was completed, the reaction was quenched by adding 20 mL of icewater. The system was extracted with 50 mL of ethyl acetate 2 times, andthe organic phases were combined, backwashed with 50 mL of saturatedbrine 2 times, dried with anhydrous sodium sulfate and concentrated togive 2.0 g of the intermediate 048-3 (89%) as a yellow solid. LCMS:258.1.

3. Synthesis of Intermediate 048-4

The intermediate 048-3 (80 mL) (2.0 g, 7.76 mmol) as a raw material wasdissolved in isopropanol (20 mL) in a 250 mL of single-necked flaskunder nitrogen, followed by sequentially adding the intermediate 006-4(1.72 mL, 9.24 mmol) and p-toluenesulfonate (1.44 g, 8.36 mnol). Thereaction was then heated to 105° C., and maintained for 2.5 h. After thereaction was completed, the reaction system was cooled to roomtemperature. The reaction mixture was filtered, and the filter cake wascollected, washed with 20 mL of isopropyl alcohol once, and washed with20 mL of acetonitrile once. The filter cake was dried to give 1.9 g ofthe intermediate 048-4 (60%) as a yellow solid. LCMS: 408.1.

4. Synthesis of Intermediate 048-5

The intermediate 048-4 (1.0 g, 2.54 mmol) as a raw material wasdissolved in NMP (20 mL) in a 50 mL of single-necked flask undernitrogen, followed by sequentially addition of anhydrous potassiumcarbonate (1.01 g, 7.36 mmol) and the intermediate 001-10 (322 mg, 3.15mmol). The reaction was heated to 105° C. and maintained for 2 h. Afterthe reaction was completed, the reaction mixture was cooled to roomtemperature. Next, the reaction was quenched with 20 mL of ice water.The filter cake was filtered by suction, collected, washed with 20 mL ofwater once and dried to give 0.9 g of crude product 048-5 (75%) as a redsolid. LCMS: 490.2.

5. Synthesis of Intermediate 048-6

The intermediate 048-5 (900 mg, 1.84 mmol) as a raw material wasdissolved in 10 mL of water and 30 mL of methanol in a 100 mLsingle-necked flask, followed by sequentially adding iron powder (0.618g, 11.1 mmol) and ammonium chloride (68 mg, 1.27 mmol). The reaction washeated to 85° C. and carried out for 2 h. After the reaction wascompleted, the reaction was cooled to room temperature, and the ironpowder was removed. Next, the filtrate was collected, spin-dried toremove most of the methanol and then extracted with 50 mL of DCM twice.The organic phases were combined and concentrated to give 0.25 g ofcrude product 048-6 (30%) as a yellow solid,

6. Synthesis of Compound 48

Under a nitrogen atmosphere, the intermediate 048-6 (250 mg, 0.54 mmol)as a raw material was dissolved in 50 mL of THF in a 250 mL three-neckedflask, followed by addition of DIPEA (140 mg, 1.08 mmol). The reactionmixture was cooled to 0° C., and acryloyl chloride (48 mg, 0.54 mmol)was added dropwisely. After the reaction was carried out at roomtemperature for 1 h, 2 mL of ice water was added to quench the reaction.The reaction mixture was concentrated and the crude product was purifiedby high pressure liquid chromatography (column model: Waters X-bridgeRP18, 19×150 mm, 5 um; mobile phase: water (0.05% ammonia)/acetonitrile,20% acetonitrile to 25% acetonitrile, 5 min, 15 mL/min; detectionwavelength: 254 nm). The obtained product was collected and dried togive compound 48.

The compound 48 was dissolved in an excessive dilute HCl (10 mL, 0.1 M)and freeze dried to give 48.5 mg of hydrochloride (HCl)_(n) of compound48 (16%) as a yellow solid. LCMS (parent molecule) C₂H₃₆ClN₇O₂: (ES,m/z): [M+H]⁺=550. ¹H-NMR (300 MHz, DMSO-D₆, ppm) δ 1.34-1.47 (m, 3H),2.64 (s, 3H), 2.74-2.76 (d, J=4.8 Hz, 6H), 3.33-3.40 (d, J=22.5 Hz, 4H),3.72-3.87 (d, J=45.6 Hz, 3H), 4.30-4.37 (m, 2H), 5.68-5.73 (m, 1H),6.20-6.26 (m, 1H), 7.00 (s, 1H), 7.16-7.29 (m, 3H), 7.35-7.37 (t, J=6.3Hz, 1H), 7.60-7.63 (t, J=8.1 Hz, 1H), 8.27-8.29 (d, J=5.1 Hz, 2H),8.57-8.62 (d, J=14.7 Hz, 2H), 8.75 (s, 1H), 9.90 (s, 1H), 10.59 (s, 1H).

Example 49

1. Synthesis of Intermediate 049-1

Sodium hydride (60%, dispersed in mineral oil) (400 mg, 16.7 mmol) wasdissolved in anhydrous DMF (80 mL) in a 250 mL of three-necked flask atroom temperature under a nitrogen atmosphere, and the reaction mixturewas cooled to 0° C. in ice-water bath. The intermediate 048-2 (1.5 g,6.53 mmol) as a raw material was added to the reaction system withstirring at 0° C. for 30 minutes. Methylsulfonyl chloride (MsCl) (1.1 g,9.60 mmol) was added dropwisely to the reaction system and then thereaction carried out at room temperature for 2 hours. The reaction wasquenched by adding 200 mL of ice water, then extracted with 100 mL ofethyl acetate 3 times. The organic phases were combined, andsequentially washed with 100 mL of water twice and 100 mL of brine once,and finally dried over anhydrous sodium sulfate and concentrated. Thecrude product was purified by silica gel column chromatography (eluent:EA/PE=1: 50-1:5) to give 0.8 g of the intermediate 049-1 (40%) as ayellow solid.

2. Synthesis of Intermediate 049-4

The reaction step and condition of synthesizing the compound 049-4 fromthe intermediate 049-1 were the same as those of the second to fourthsteps in Example 3. LCMS (049-4): 510.2.

3. Synthesis of Compound 49

Under a nitrogen atmosphere, the intermediate 049-4 (500 mg, 0.98 mmol)as a raw material was dissolved in dichloromethane (50 mL) in 100 mL ofa three-necked flask at room temperature, followed by adding DIPEA (255mg, 1.97 mmol). The reaction system was cooled to 0° C., and propylchloride (89 mg, 0.98 mmol) was added dropwisely therein at 0° C. Then,the reaction was continued for 20 minutes at 0° C. After the reactionwas completed, the reaction system was concentrated and the crudeproduct was purified by silica gel column chromatography, and theproduct was concentrated to dryness to give compound 49.

The obtained product 49 was dissolved in 3 mL (0.1 M) of aqueoussolution of hydrochloric acid, followed by that the reaction mixture wasstirred at room temperature for 1 hour and freeze dried to give 108 mgof the hydrochloride salt of compound 49, 49.(HCl)_(n) (18%) as a yellowsolid. LCMS (parent molecule) C₂H₃₃N₇O₄S: (ES, m/z): [M+H]=564. ¹H-NMR:(300 MHz, DMSO-D₆, ppm) δ 10.38 (s, 1H), 9.84 (s, 1H), 8.75-8.74 (m,1H), 8.59 (s, 1H), 8.56-8.39 (m, 3H), 7.91-7.88 (d, J=9 Hz, 1H),7.51-7.33 (m, 3H), 7.14-7.05 (m, 1H), 6.98 (s, 1H), 6.23-6.17 (d, J=10Hz, 1H), 5.71-5.67 (d, J=4.5 Hz, 1H), 3.97 (s, 1H), 6.98 (s, 3H), 3.60(s, 3H), 3.32 (s, 4H), 2.76 (s, 6H), 2.51 (s, 1H).

Example 50

1. Synthesis of Intermediate 050-2

200 mL of concentrated hydrochloric acid and the intermediate 050-1 (2.0g, 13.1 mmol) were sequentially added into a 500 mL single-necked flaskunder nitrogen, and then the reaction system was heated to 85° C.overnight. After the reaction was completed, the reaction system wascooled to room temperature, and directly concentrated to dryness to give1.3 g of the intermediate 050-2 (74%) as a white solid. LCMS: 135.0

2. Synthesis of Intermediate 050-3

25 mL of isopropyl alcohol, the intermediates 001-5 (1.3 g, 9.69 mmol)and 050-2 (718 mg, 4.82 mmol), and DIPEA (5.0 g, 38.7 mmol) weresequentially added into a 50 mL of single-necked flask under nitrogen,and then the reaction system was heated to 45° C. overnight. After thereaction was completed, the reaction system was cooled to a roomtemperature, quenched by adding 100 mL of ice water, extracted with 200mL of dichloromethane three times. The organic phases were combined andbackwashed back with 500 mL of saturated brine three times, dried oversodium sulfate, concentrated to dryness, so as to give the crudeproduct. The crude product was purified by silica gel columnchromatography (eluent: DCM/MeOH=3:1-1:1). The product was concentratedto dryness to give 0.650 g of the intermediate 050-3 (27%) as a yellowsolid. LCMS: 247.0.

3. Synthesis of Compound 50

The reaction steps and conditions of synthesizing the compound 50 andhydrochloride (HCl) of compound 50 from the intermediate 050-3 were thesame as those of the third step to the sixth step in Example 48, exceptthat the intermediate 048-3 in the example 48 was replaced with theintermediate 050-3 in the this step. The analysis data of thehydrochloride (HCl) of compound 50: LCMS (parent molecule) C₂₆H₃₀N₈O₃:(ES, m/z): [M+H]⁺=503. ¹H-NMR: (300 MHz, DMSO-d, ppm) δ 2.67 (s, 3H),2.75 (s, 3H), 2.76 (s, 3H), 3.29-3.36 (m, 4H), 3.83 (s, 3H), 4.08 (s,3H), 5.66-5.70 (m, 1H), 6.15-6.21 (m, 1H), 7.02 (s, 1H), 7.14-7.24 (m,2H), 7.35-7.39 (m, 1H), 7.53-7.55 (m, 1H), 7.82-7.84 (d, J=7.5 Hz, 1H),8.21 (s, 1H), 8.28-8.30 (m, 1H), 9.97 (s, 1H), 10.63-10.65 (br s, 1H).

Example 51

1. Synthesis of Intermediate 051-2

The intermediate 051-1 (10.0 g, 54.7 mmol) as a raw material wasdissolved in DMF (500 mL) in a 1000 mL of four-necked flask at roomtemperature under a nitrogen atmosphere, then sequentially addingpotassium hydroxide (19.0 g, 338.6 mmol) and iodine (21.5 g, 84.8 mmol).Then, the reaction was carried out overnight at room temperature. Afterthe reaction was completed, 500 mL of a 10% aqueous solution of sodiumthiosulfate was added to the reaction mixture to quench the reaction.The reaction mixture was extracted with 500 mL of ethyl acetate threetimes. The organic phases were combined and washed with 500 mL ofsaturated brine once, then dried over anhydrous sodium sulfate andconcentrated to give 15.3 g of crude product 051-2 (74%) as an off-whitesolid. LCMS: 245.0.

2. Synthesis of Intermediate 051-3

The intermediate 051-2 (4.0 g, 16.4 mmol) as a raw material wasdissolved in 60 mL of anhydrous tetrahydrofuran in 250 mL of athree-necked flask at room temperature, and the reaction was cooled to0-5° C. with ice-salt. After sodium hydride (720 Mg, 30.0 mmol) wasadded into the reaction system, the reaction system was maintained at aninternal temperature of 0-5° C. and stirred for 1 h. Next, iodoethane(3.1 g, 19.9 mmol) was added to the reaction system at 0-5° C. followedby stirring for 3h. After the reaction was completed, the reaction wasquenched by adding 100 mL of water. The reaction mixture was extractedthree times with 150 mL of ethyl acetate. The organic phases werecombined, dried over anhydrous sodium sulfate, concentrated to dryness.The crude product was purified by silica gel column chromatography(eluent: EA:PE=1:50) to give 3.6 g of the intermediate 051-3 (81%) as apale yellow oil. LCMS: 273.0

3. Synthesis of Intermediate 051-4

The intermediate 051-3 (3.6 g, 13.2 mmol) as a raw material wasdissolved in 1,4-dioxane (50 mL) in 250 mL of a three-necked flask undernitrogen, followed by sequentially adding hexamethylditin (5.19 g, 15.84mmol) and tetrakis(triphenylphosphine)palladium (1.5 g, 1.30 mmol) intothe reaction system. Then, the reaction was heated to 105° C. andmaintained overnight. After the reaction was completed, the reactionsystem was cooled to 25° C. with ice-water. The reaction mixture wasconcentrated to dryness and the resulting residue was purified by silicagel column chromatography (eluent: PE/EA=60:1) to give 1.9 g of theintermediate 051-4 (46%) as yellow oil. LCMS: 311.0.

4. Synthesis of Intermediate 051-5

The intermediate 001-5 (1.9 g, 6.15 mmol) as a raw material wasdissolved in 1,4-dioxane (50 mL) in 100 mL of a three-necked flask atroom temperature under nitrogen, followed by sequentially adding theintermediate 051-4 (0.9 g, 6.04 mmol) andtetrakis(triphenylphosphine)palladium (0.71 g, 0.61 mmol) into thereaction system. Then, the reaction was heated to 105° C. and maintainedovernight. After the reaction system was cooled to 25° C. withice-water, the reaction mixture was concentrated to dryness. Theresulting residue was purified by silica gel column chromatography(eluent: PE:EA=25:1) to give 680 mg of the intermediate 051-5 (43%) as ayellow solid. LCMS: 259.1.

5. Synthesis of Compound 51

The reaction steps and conditions of synthesizing the compound 51 andhydrochloride (HCl)_(n) of compound 51 from the intermediate 051-5 werethe same as those of the sixth step to the ninth step in Example 1,except that the intermediate 001-6 in the example 1 was replaced withthe intermediate 051-5 in the this step. The analysis data of thehydrochloride (HCl) of compound 51: LCMS (parent molecule) C₂₈H₃₄N₈O₂:(ES, m/z) [M+H]⁺=515. ¹H-NMR (300 MHz, DMSO-d₆, ppm) δ 10.44 (s, 1H),9.92 (s, 1H), 9.03 (m, 1H), 8.38-8.44 (m, 3H), 7.77-7.80 (m, 1H),7.42-7.52 (m, 2H), 7.24-7.29 (m, 1H), 7.11-7.19 (m, 1H), 6.99 (s, 1H),6.16-6.22 (m, 1H), 5.67-5.70 (m, 1H), 4.59-4.67 (m, 2H), 3.90 (s, 3H),3.34 (s, 4H), 2.75-2.76 (m, 6H), 2.65 (s, 3H), 1.45-1.50 (m, 3H).

Example 52

1. Synthesis of Intermediate 052-4

The intermediate 052-1 (3.16 g, 19.9 mmol), dichloromethane (150 mL) andDMF (0.3 mL) were added to a 250 mL of three-necked flask undernitrogen. The reaction system was cooled to 0° C., and the intermediate052-2 (3.02 g, 23.8 mmol) was added thereto, then the reaction wascarried out for 2h. Next, DIPEA (12.9 g, 99.8 mmol) and intermediate052-3 (2.44 g, 20.0 mmol) were added at 0° C., and the reaction waswarmed up to room temperature and carried out overnight. 100 mL of icewater was added to quench the reaction, and the reaction mixture wasextracted with 200 mL of DCM three times. The organic phases werecombined and washed three times with 300 mL of saturated brine, andconcentrated to dryness. The crude product was purified by silica gelcolumn chromatography (eluent: EA/PE=1:5-1:1) to give 2.0 g ofintermediate 052-4 (38%) as a white solid. LCMS: 263.1.

2. Synthesis of Intermediate 052-5

30 mL of phosphorus oxychloride and the intermediate 052-4 (2.0 g, 7.61mmol) were sequentially added to a 100 mL of single-necked flask at roomtemperature under nitrogen, and then the reaction mixture was heated to110° C. and maintained overnight. The reaction was cooled to roomtemperature and then 100 mL of ice water was added to quench thereaction. The reaction mixture was extracted with 100 mL of methylenechloride three times. The organic phases were combined and backwashedwith 200 mL of saturated brine three times, dried over anhydrous sodiumsulfate, concentrated to dryness. The crude product was purified bysilica gel column chromatography (elution: DCM/MeOH=20:1-10:1) to give1.14 g of the intermediate 052-5 (61%) as a white solid. LCMS: 245.1.

3. Synthesis of Compound 52

The reaction steps and conditions of synthesizing the compound 52 andhydrochloride (HCl)_(n) of compound 52 from the intermediate 052-5 werethe same as those of the six step to the ninth step in Example 1, exceptthat the intermediate 001-6 in the example 1 was replaced with theintermediate 052-5 in the this step. The analysis data of thehydrochloride (HCl) of compound 52: LCMS (parent molecule) C₂₇H₃₂N₈O₂(ES, m/z): [M+H]⁺=501. ¹H-NMR: (300 MHz, DMSO-d₆, ppm) δ 2.58 (s, 3H),2.67 (s, 3H), 2.74 (s, 3H), 2.76 (s, 3H), 3.26-3.48 (m, 4H), 3.84 (s,3H), 5.15-5.69 (m, 1H), 6.15-6.21 (m, 1H), 7.02 (s, 1H), 7.14-7.33 (m,3H), 7.55-7.58 (d, J=6.6 Hz, 1H), 7.96-7.99 (d, J=9 Hz, 1H), 8.23-8.25(m, 2H), 9.70-9.78 (br s, 1H), 10.00 (s, 1H), 10.25-10.29 (m, 1H), 10.72(br s, 1H).

Example 53

1. Synthesis of Intermediate 053-3

The intermediate 053-1 (2.47 g, 20.0 mmol) as a raw material wasdissolved in 30 mL of 1,2-dichloroethane (DCE) in 100 mL of athree-necked flask at room temperature, followed by adding theintermediate 053-2 (2.60 g, 15.0 mmol) and at room temperature, addingsodium triacetoxyborohydride (NaBH(OAc)₃) in batches. After stirring 3 hat room temperature, the reaction was completed. The reaction mixturewas filtered, and the filtrate was rotovapped. The obtained mixture wasextracted with 30 mL of ethyl acetate three times. Next, the resultingmixture was extracted three times with 30 mL of ethyl acetate, and theorganic phases were combined, dried over sodium sulfate and subjected torotary evaporation. The resulting residue was purified with Pre-HPLC(column: C18 silica gel; mobile phase: acetonitrile/water (5%trifluoroacetic acid); 10% acetonitrile to 50% acetonitrile; 30 min;detection wavelength: 220 nm) to give 3.0 g of the intermediate 053-3(61%) as a yellow oil. LCMS: 245.2.

2. Synthesis of Intermediate 053-4

The intermediate 053-3 (3.0 g, 12.3 mmol) as a raw material wasdissolved in 100 mL of dichloromethane at room temperature and then 3 mLof trifluoroacetic acid (TFA) was added to the system. Next, thereaction was carried out at room temperature for 2 h. After the reactionwas completed, the reaction system was subjected to rotary evaporationto give 2.0 g of the intermediate 053-4 (67%) as a brown oil. LCMS:145.1.

3. Synthesis of Intermediate 053-5

The intermediate 0534 (1.2 g, 4.95 mmol) as a raw material was dissolvedin 20 mL of NMP at room temperature in a 50 mL of single-necked flask,followed by adding the intermediate 006-5 (19.5 g, 49.6 mmol) andanhydrous potassium carbonate (2.06 g, 14.9 mmol) into the reactionsystem. The reaction was heated to 100° C. and then carried out for 2 h.After the reaction was completed, the reaction was quenched by adding100 mL of ice water to the mixture. A solid was precipitated, collected,dissolved in 200 mL of methylene chloride and washed once with 100 mL ofsaturated sodium chloride solution. The organic phases were dried oversodium sulfate and spin-dried to give 1.2 g of the intermediate 053-5(47%) as a brown solid. LCMS: 518.2.

4. Synthesis of Intermediate 053-6

The intermediate 053-5 (0.50 g, 0.97 mmol) as a raw material wasdissolved in 40 mL of dichloromethane in a 100 mL of single-necked flaskat room temperature and then imidazole (528 mg, 7.76 mmol) was added tothe reaction solution. The reaction system was cooled to 0° C.,tert-butyldimethylsilyltrifluoromethanesulfonate (TBSOTf) (2.56 g, 9.68mmol) was added thereto and the mixture was stirred overnight at roomtemperature. After the reaction was completed, the mixture was dilutedwith 100 mL of methyl chloride. The organic phases were washed with 40mL of saturated sodium bicarbonate solution three times and 30 mL ofsaturated sodium chloride solution twice, respectively. The organicphases were dried over anhydrous sodium sulfate and concentrated todryness. The resulting residue was purified by silica gel chromatography(eluent: EA:PE=1:1) to give 210 mg of the intermediate 053-6 (34%) as ared solid. LCMS: 632.3.

5. Synthesis of Intermediate 053-7

The intermediate 053-6 (210 mg, 0.33 mmol) as a raw material wasdissolved in 30 mL of anhydrous methanol in a 50 mL single-necked flask,followed by adding ammonium formate (210 mg) and palladium on carbon(210 mg, 5% Pd). Next, the reaction was carried out for 3h. The reactionmixture was filtered and the filtrate was subjected to rotaryevaporation. The resulting mixture was dissolved in 50 mL of methylenechloride. The mixture was washed with 30 mL of saturated brine twice andthe organic phases were dried over sodium sulfate and concentrated todryness to give 195 mg of the intermediate 053-7 (97%) as a yellowsolid. LCMS: 602.4.

6. Synthesis of Intermediate 053-8

In a 50 mL of three-necked flask, the intermediate 053-7 (195 mg, 0.32mmol) as a raw material was dissolved in 30 mL of THF, followed byadding DIPEA (83 mg, 0.64 mmol). The reaction system was cooled to 0° C.with ice water, and then acryloyl chloride (29.2 mg, 0.32 mmol) wasadded thereto. Next, the mixture was stirred at room temperature for 30min. After the reaction was completed, 2 drops of water were added tothe reaction system to quench the reaction and subjected to rotaryevaporation to give 300 mg of crude product 053-8. LCMS: 656.4.

7. Synthesis of Compound 53

The intermediate 053-8 (0.3 g, 0.46 mmol) as a raw material wasdissolved in 40 mL of THF at room temperature followed by addition oftetrabutylammonium fluoride (360 mg, 13.1 mmol), and then the reactionwas stirred at room temperature for 2.5 h. After the reaction wascompleted, the reaction was subjected to rotary evaporation. Theresulting residue was purified with high pressure Prep-HPLC (column:Waters Sunfire C18, 19×150 mm, 5 um; mobile phase: acetonitrile/water(0.05% trifluoroacetic acid); 12% acetonitrile to 40% acetonitrile; 7min; 15 mL/min; detection wavelength: 254 nm). The fractions of productwere collected and most of the acetonitrile was removed. The pH value ofmixture was adjusted to 9 to 10 with a saturated aqueous solution ofsodium bicarbonate, and extracted twice with 100 mL of DCM. The organicphase extracted dried over anhydrous sodium sulfate, to give compound53. LCMS: 541.64.

The compound 53 was dissolved in 10 mL of aqueous solution ofhydrochloric acid (0.1 N), then the reaction mixture was freeze dried togive 8.3 mg of the hydrochloride (HCl) of compound 53 (3%) as a yellowsolid. LCMS (parent molecule) C₃H₃₅N₇O₃: (ES, m/z): 542.6 [M+H]⁺.¹H-NMR: (300 MHz, D₂O, ppm) δ7.91 (s, 2H), 7.74 (s, 1H), 7.66-7.45 (m,1H), 7.25-7.17 (m, 2H), 7.04-6.98 (m, 2H), 6.72-6.60 (m, 1H), 6.58-6.55(m, 1H), 6.30 (d, J=17.1 Hz, 1H), 5.88 (d, J=10.5 Hz, 1H), 4.59 (s, 1H),3.89 (s, 3H), 3.83-3.60 (m, 2H), 3.50 (s, 3H), 3.39 (s, 5H), 3.27-3.07(m, 2H), 2.70 (s, 2H), 2.64-1.99 (m, 2H).

Example 54

1. Synthesis of Intermediate 054-3

The raw material of N—BOC-(methylamino)acetaldehyde (the intermediate054-1) (1.039 g, 6.00 mmol) was dissolved in 30 mL of DCE in a 50 mLsingle-necked flask under a nitrogen atmosphere at 0° C., followed byadding N-(2-methoxyethyl) methylamine (the intermediate 054-2) (534 mg,5.99 mmol). After the reaction mixture was stirred at 0° C. for 30minutes, NaBH(OAc)₃ (1.908 g, 6.00 mmol) was slowly added to thereaction system in batches, and then the reaction was carried out at 0°C. for 1 hour. The reaction was heated to 25° C. and maintained for 8hours. After the reaction was completed, 50 mL of ice water was added toquench the reaction. The reaction mixture was extracted with 20 mL ofethyl acetate three times. The combined organic phases were washed with20 mL of saturated brine once, dried over anhydrous sodium sulfate andconcentrated to dryness to give 0.7 g of the intermediate 054-3 (47%) asa crude oil in yellow. LCMS: 246.3.

2. Synthesis of Intermediate 054-4

The intermediate 054-3 (700 mg, 2.84 mmol) was dissolved in 20 mL ofanhydrous methanol in a 50 mL single-necked flask at room temperature. 3mL of concentrated hydrochloric acid was slowly added to the reactionsystem under ice bath and the reaction was carried out for 2 h. Afterthe reaction was completed, the system was concentrated to dryness togive 0.4 g of crude product 054-4 as a yellow solid. LCMS: 182.6.

3. Synthesis of Intermediate 054-5

The intermediate 054-4 (400 mg, 1.02 mmol) as a raw material wasdissolved in 5 mL of NMP in 100 mL three-necked flask at roomtemperature under a nitrogen atmosphere, followed by sequentially addingthe intermediate 006-5 (400 mg, 2.37 mmol) and K₂C₀₃ (907 mg, 6.56 mmol)into the reaction system. The reaction system was heated to 105° C. andcarried out for 2 hours. After completion of the reaction, the reactionwas cooled to room temperature, quenched by adding 30 mL of water. Thereaction mixture was extracted with 30 mL of ethyl acetate three times.The organic phases were combined, washed with 30 mL of saturated brinethree times, dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified by silica gel column chromatography(eluent: DCM/MeOH=15:1) to give 100 mg of the intermediate 054-5 (19%)as a white solid. LCMS: 519.6.

4. Synthesis of Intermediate 054-6

The intermediate 054-5 (100 mg, 0.19 mmol) was dissolved in 10 mL ofanhydrous methanol in a 50 mL single-necked flask at room temperature,followed by adding Pd/C containing water (200 mg, 5% Pd) and ammoniumformate (200 mg, 0.38 mmol) into the reaction system. The reaction wascarried out at room temperature for 2h. After the reaction wascompleted, the reaction mixture was undergone a sucking filtration andthe filtrate was collected and concentrated to dryness to give 80 mg ofthe intermediate 054-6 (85%) as a white solid. LCMS: 489.6.

5. Synthesis of Compound 54

The intermediate 054-6 (62 mg, 0.48 mmol) as a raw material wasdissolved in 10 mL of dichloromethane in a 50 mL single-necked flask at−5° C., then adding DIPEA (62 mg, 0.48 mmol). And then allyl chloride(13 mg, 0.14 mmol) was added dropwisely to the reaction system. Next,the reaction was carried out at 0° C. for 2h. After completion of thereaction, the reaction system was quenched with 1 mL of water, thereaction mixture was concentrated to dryness, and the residue waspurified by high pressure preparation Prep-HPLC(Column: Waters X-bridgeRP18, 19×150 mm, 5 um; mobile phase: water (10 mM NH₄HCO₃+0.05%ammonia)/acetonitrile, 56% acetonitrile to 61% acetonitrile, 7 min, 20mL/min; detection wavelength: 254 nm), and the resulting organic phaseswere subjected to rotary evaporation to give compound 54.

The compound 54 was dissolved in the aqueous solution of hydrochloricacid solution (1 M), and the reaction mixture was stirred at roomtemperature for 30 minutes and freeze dried to give 12.3 mg of thehydrochloride of compound 54 (13%) as a yellow solid. LCMS (parentmolecule) C₃₀H₃₇N₇O₃: (ES, m/z): 544 [M+H]⁺. ¹H-NMR: (DMSO-D₆, 300 MHz,ppm) 810.34-10.31 (m, 1H), 9.89 (s, 1H), 8.80 (s, 1H), 8.39-8.23 (m,3H), 7.58-7.61 (m, 1H), 7.42-7.40 (m, 1H), 7.20-7.33 (m, 2H), 7.03-7.13(m, 2H), 6.20-6.25 (m, 1H), 5.70-5.74 (m, 1H), 3.93 (s, 4H), 3.85 (s,4H), 3.70 (s, 4H), 3.30 (s, 3H), 3.40 (s, 3H), 2.80 (s, 3H), 2.73 (s,3H).

Example 55

1. Synthesis of Intermediate 055-2

The intermediate 055-1 (2 g, 15.13 mmol) was dissolved in 100 mL oftetrahydrofuran (THF) in a 250 mL three-necked flask at room temperatureunder a nitrogen atmosphere, then adding NaH (65%) (620 mg, 25.83 mmol)in batches at room temperature. Next, the reaction was maintained atroom temperature for h. After the reaction mixture was cooled to 0° C.,the intermediate 001-5 (3.36 g, 22.55 mmol) was added thereto and thereaction was carried out for 2h. After completion of the reaction, thereaction mixture was quenched by adding 100 mL of ice water. The mixturewas extracted with 100 mL of ethyl acetate three times. The organicphases were combined and washed with 50 mL of saturated brine threetimes, dried over anhydrous sodium sulfate and concentrated. The crudeproduct was purified through silica gel column chromatography (EA 1PE=1: 10-1:3) to give 1.5 g of the intermediate 055-2 (41%) as a paleyellow solid. LCMS: 245.0.

2. Synthesis of Intermediate 055-3

The intermediate 055-2 (1.5 g, 6.13 mmol) as a raw material wasdissolved in 150 mL of isopropanol in a 250 mL three-necked flask undernitrogen atmosphere, followed by sequentially adding the intermediate006-4 (1.13 g, 6.07 mmol) and p-toluenesulfonate acid (1.13 g, 6.07mmol) into the reaction system. The reaction was heated to 105° C. andcarried out for 2 h. After the reaction was completed, the reactionmixture was cooled to room temperature, and filtered by suction. Thefilter cake was collected, sequentially washed with 30 mL of water twiceand 30 mL of n-hexane twice, and dried to give 2 g of the intermediate055-3 (83%) as a yellow solid. LC MS: 381.0.

3. Synthesis of Intermediate 055-4

The intermediate 055-3 (2.0 g, 5.07 mmol) as a raw material wasdissolved in 60 mL of NMP in a 100 mL three-necked flask at roomtemperature under a nitrogen atmosphere, then addingN,N,N′-trimethylethylenediamine (680 mg, 6.66 mmol) and anhydrouspotassium carbonate (2.1 g, 15.2 mmol) into the reaction system. Thereaction was heated to 100° C. and carried out for 2 h. After thereaction was completed, the reaction was cooled to room temperature andquenched by adding 200 mL of ice water to the reaction mixture. Themixture was filtered by suction, and the filter cake was collected,sequentially washed with 50 mL of water twice and 50 mL of n-hexanetwice. The reaction mixture was dried to give 1.2 g of the intermediate055-4 (50%) as a brown solid. LCMS: 477.0.

4. Synthesis of Intermediate 055-5

The intermediate 055-4 (1.2 g, 2.52 mmol), iron powder (853 mg, 15.3mmol) and ammonium chloride (93 mg, 2.53 mmol) were sequentially addedinto 12 mL of ethanol and 4 mL of water in a 50 mL three-necked flask atroom temperature under a nitrogen atmosphere. Next, the reaction wascarried out at 80° C. for overnight. After the reaction was completed,the reaction system was cooled to room temperature. The mixture wasfiltered by suction, and the filtrate was collected, concentrated todryness. The crude product was purified by flash chromatography(chromatography column: C18 silica gel; mobile phase: acetonitrile/water(0.05% trifluoroacetic acid); 35% acetonitrile to 50% acetonitrile; 15min; detection wavelength: 254 nm) to give 1.02 g of the intermediate055-5 (72%) as a yellow solid. LCMS: 447.0.

5. Synthesis of Compound 55

The intermediate 055-6 (280 mg, 0.50 mmol) as a raw material wasdissolved in 20 mL of anhydrous THF at room temperature in a 100 mLthree-necked flask at room temperature under a nitrogen atmosphere,followed by adding N,N-diisopropylethylamine (DIPEA) (193.5 mg, 1.50mmol). After the reaction mixture was cooled to 0° C., acetyl chloride(40.5 mg, 0.45 mmol) was dissolved in 2 mL of tetrahydrofuran at 0° C.and the resulting solution was added dropwisely to the reaction system.Next, the reaction was stirred at 0° C. for 1 h. After the reaction wascompleted, the mixture was quenched with 1 mL of water and the residuewas concentrated to dryness. The crude product was purified by highpressure preparation HPLC (column: Waters X-bridge RP 18, 19×150 mm,mobile phase: water (10 mM NH₄HCO₃+0.05% ammonia)/acetonitrile, 50%acetonitrile to 57% acetonitrile, 5 min, 20 mL/min; detectionwavelength: 254 nm). The resulting organic phases were subjected torotary evaporation to give compound 55. LCMS: 501.0.

Compound 55 was dissolved in 7.2 mL of 0.01 M aqueous solution ofhydrochloric acid, and freeze dried to give 20 mg of the hydrochloride(HCl)_(n) of compound 55 as a yellow solid. LCMS (parent molecule)C₂₇H₃₂N₈O₂: (ES, m/z): 501 [M+H]⁺. ¹H-NMR: (DMSO-D₆, 300 MHz, ppm):11.09-11.17 (m, 1H), 10.82 (br s, 1H), 10.14 (br s, 1H), 8.27 (br s,1H), 8.12-8.15 (d, J=7.2 Hz, 1H), 7.92-7.94 (d, J=7.8 Hz, 1H), 7.62-7.67(m, 1H), 7.39-7.44 (m, 1H), 7.24-7.33 (m, 1H), 7.04 (s, 1H), 6.91 (br s,1H), 6.10-6.16 (m, 1H), 5.62-5.66 (m, 1H), 3.86 (s, 3H), 3.40 (m, 4H),2.76 (s, 3H), 2.74 (s, 3H), 2.68 (s, 3H), 2.66 (s, 3H).

Example 56

1. Synthesis of Intermediate 056-2

Under a nitrogen atmosphere, 2-nitroacetophenone 056-1 (8.5 g, 51.47mmol) was added to 80 mL of DMF in a 250 mL three-necked flask at roomtemperature, followed by adding DMF-DMA (8.0 g, 67.2 mmol) into thereaction system. The reaction temperature was heated to 110° C. for 2 h.After detecting the reaction was completed, the reaction mixture wascooled to room temperature. The reaction was quenched with 100 mL of icewater and extracted with 100 mL of ethyl acetate three times. Theorganic phases were collected, washed with saturated brine three times,dried over anhydrous sodium sulfate three times and concentrated. Theresidue was washed with 200 mL of n-hexane once and filtered by suction.The filter cake was collected and dried to give 7.6 g of theintermediate 056-2 (67%) as a yellow solid. LCMS: 166.0.

2. Synthesis of Intermediate 056-4

The intermediate 056-2 (75.6 g, 34.5 mmol) was dissolved in 100 mL ofanhydrous ethanol in a 250 mL three-necked flask at room temperatureunder a nitrogen atmosphere, followed by adding cyclohexene (theintermediate 056-3) (14.2 g, 172.9 mmol) and palladium on carboncontaining water (18.7 g, 10% Pd) into the reaction system at roomtemperature. The reaction was heated to reflux for 2 h. After thereaction was completed, the mixture was cooled to room temperature andthen filtered by suction. The filtrate was collected and concentrated todryness. The residue was washed with 100 mL of the mixed solvent(EA/PE=1:2) once. The solid was filtered by suction, and the filter cakewas dried to give 4.2 g of the intermediate 056-4 (84%) as a yellowsolid. LCMS: 146.1.

3. Synthesis of Intermediate 056-5

Under a nitrogen atmosphere, the intermediate 056-4 (3.0 g, 20.7 mmol)as a raw material was dissolved in 50 mL of N,N-dimethylformamide (DMF)in a 100 mL single-necked flask at room temperature, and then thereaction system was cooled to 0° C. and NaH (65%, dispersed in a mineraloil) (2.3 g, 95.8 mmol) was added thereto. The reaction was maintainedat 0° C. for 30 min. Next, 2,4-dichloropyrimidine (the intermediate001-5) (6.0 g, 40.3 mmol) was dissolved in 50 mL of DMF and theresulting solution was added dropwisely to the reaction system at 0° C.The reaction was carried out at 0° C. for 2h until the reaction wasdetected to confirm the reaction was completed. The reaction mixture waspoured into 100 mL of aqueous solution of saturated ammonium chloride toquench the reaction, and the system was extracted with 100 mL of ethylacetate three times. The organic phases were combined, washed with 100mL of saturated brine three times, dried over anhydrous sodium sulfateand concentrated. The crude product was purified by flash columnchromatography (column: silica gel; mobile phase: ethylacetate/petroleum ether; 50% ethyl acetate to 85% ethyl acetate; 30 min;detection wavelength: 254 nm) to give 1 g of the intermediate 056-5(19%) as a white solid. LCMS: 258.0.

4. Synthesis of Compound 56

The reaction steps and conditions for the synthesis of final compound 56and its hydrochloride 56. (HCl)_(n) from the intermediate 056-5 were thesame as those in the second and third steps of example 55, except thatthe intermediate 055-3 in example 55 was replaced with the intermediate056-5. Analytical data for the hydrochloride 56.(HCl)_(n): LCMS (parentmolecule) C₂₈H₃₁N₇O₃: (ES, m/z): 514 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆,ppm) δ 10.45 (br s, 1H), 9.73 (s, 1H), 8.92 (s, 1H), 8.67-8.65 (d, J=5.1Hz, 1H), 8.35 (s, 1H), 8.30-8.28 (d, J=7.8 Hz, 1H), 8.21-8.19 (d, J=7.5Hz, 1H) 7.71-7.64 (m, 2H), 7.47-7.7.42 (m, 4H), 7.17-7.02 (m, 2H), 6.92(s, 1H), 6.28-6.22 (m, 2H), 5.73-5.60 (dd, J=10.2 Hz, 2.1 Hz, 1H), 3.88(s, 3H), 327 (m, 4H), 2.72-2.71 (d, J=4.8 Hz, 6H), 2.65 (s, 3H).

Example 57

1. Synthesis of Intermediate 057-2

Under a nitrogen atmosphere, deuterated dimethylamine hydrochloride (1.5g, 17.2 mmol) was added to 50 mL of 1,2-dichloroethane in a 100 mLthree-necked flask at room temperature, then adding the intermediate057-1 (3.0 g, 17.3 mmol) into the reaction system. The reaction wascarried out at room temperature for 2 h. After the reaction system wascooled to 0° C., sodium triacetoxyborohydride (5.5 g, 26.0 mmol) wasadded in batches and the reaction was heated from 0° C. to roomtemperature. Then, the reaction was stirred overnight. After detectingthe reaction was completed the next day, the reaction was quenched with100 mL of saturated aqueous solution of ammonium chloride, and thereaction mixture was extracted with 100 mL of methylene chloride twice.The aqueous phases were collected, adjusted to pH 9 with saturatedaqueous solution of sodium carbonate, extracted with 100 mL of methylenechloride three times, and the organic phases were combined, washed with100 mL of saturated brine twice, dried over anhydrous sodium sulfate andconcentrated to dryness to give 0.80 g of the intermediate 057-2 (22%)as yellow oil. LCMS: 209.2.

2. Synthesis of Intermediate 057-3

The intermediate 057-2 (800 mg, 3.85 mmol) as a raw material wasdissolved in 10 mL of anhydrous methanol in a 50 mL single-necked flaskat room temperature, followed by adding 10 mL of concentratedhydrochloric acid into the reaction system at room temperature. Thereaction was carried out for 5 h at room temperature. After detectingthe reaction was completed, the reaction mixture was concentrateddirectly to give 0.60 g of the intermediate 057-3 (87%) as a whitesolid. LCMS: 109.2.

3. Synthesis of Compound 57

The reaction steps and conditions for the synthesis of final compound 57and its hydrochloride 57.(HCl)_(n) from the intermediates 037-3 and057-3 were the same as those in the second to fifth steps of example 55,except that the intermediate 055-3 in example 55 was replaced with theintermediate 037-3 and the intermediate 001-10 in example 55 wasreplaced with the intermediate 057-3. Analytical data for thehydrochloride 57.(HCl)_(n): LCMS (parent molecule) C₂₉H₃₁ D₆ N₇O₂: (ES,m/z): 522.3 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ 10.06 (br s, 1H)9.92-9.97 (m, 2H), 8.08-8.24 (m, 3H), 7.32-7.35 (m, 1H), 7.11-7.26 (m,3H), 7.02 (s, 1H), 6.17-6.23 (br s, 1H), 5.67-5.71 (m, 1H), 3.99 (m,2H), 3.83 (s, 3H), 3.35 (m, 4H), 2.65 (s, 3H), 1.33 (s, 6H).

Example 58

1. Synthesis of Compound 58

The reaction steps and conditions for the synthesis of final compoundand its hydrochloride 58.(HCl)_(n) from the intermediates 040-2 and057-3 were the same as those in the third to fifth steps of example 55,except that the intermediate 055-3 in example 55 was replaced with theintermediate 040-3 and the intermediate 001-10 in example 55 wasreplaced with the intermediate 057-3. Analytical data for thehydrochloride 58.(HCl)_(n): LCMS (parent molecule) C₂₇H₂₆D₆N₈O₃: (ES,m/z): 523.3 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D, ppm) δ 10.47 (br s, 1H),9.84 (s, 1H), 9.29-9.42 (m, 1H), 8.43-8.45 (d, J=6 Hz, 1H), 8.18 (br s,1H), 7.83-7.51 (d, J=6.3 Hz, 1H), 7.10-7.25 (m, 3H), 6.99-7.04 (m, 2H),6.17-6.23 (m, 1H), 5.67-5.71 (m, 1H), 3.75 (s, 3H), 3.38 (s, 3H), 3.33(m, 4H), 2.73 (s, 3H).

Example 59

1. Synthesis of Intermediate 059-2

Under a nitrogen atmosphere, the intermediate 059-1 (90 g, 611.7 mmol),1500 mL of THF, triphenylphosphine (PPh₃) (176.4 g, 672.6 mmol) andtetradeuteromethanol (CD₃OD) (22.5 g, 642.9 mmol) were sequentiallyadded into a 3000 mL four-necked flask. After the reaction was cooled to0° C., DEAD (117 g, 671.8 mmol) was added dropwisely for 1 h. Thereaction was carried out at room temperature overnight. The reaction wascompleted, and 5000 mL of ice was added therein to quench the reaction.The reaction mixture was extracted with 3000 mL of ethyl acetate threetimes and the organic phases were combined, washed with 3000 mL ofsaturated brine three times, dried over anhydrous sodium sulfate andsubjected to rotary evaporation. The crude product was purified bysilica gel column chromatography (eluent: EA:PE=1:10-1:5) to give 55 gof the intermediate 059-2 (55%) as a white solid.

2. Synthesis of Intermediate of Deuterated Methylamine

The intermediate 059-2 (55 g, 335.0 mmol), water (440 mL) andconcentrated hydrochloric acid (440 mL) were sequentially added into a2000 mL single-necked flask. The reaction mixture was heated to 105° C.and then the reaction was carried out for 48 h. After completion of thereaction, the reaction was cool to room temperature. The solid wasremoved by filtration, and the filtrate was concentrated to dryness. Thecrude product was added to 100 mL of ethanol, the resulting mixture washeated to 75° C. and refluxed for 1 h and cooled to room temperature.The obtained solid was filtered by suction, and the filter cake wascollected and dried to give 12 g of deuterated methylamine hydrochloride(51%) as a white solid.

3. Synthesis of Intermediate 059-3

Deuterated methylamine hydrochloride (2.6 g, 36.86 mmol), 50 mL ofmethanol, triethylamine (Et₃N) (3.8 g, 37.6 mmol) and benzaldehyde (2 g,18.9 mmol) were sequentially added to a 250 mL three-necked flask undera nitrogen atmosphere. The reaction system was cooled to 0° C.,tetraisopropyltitanate (Ti(Oi-Pr)₄) (10.8 g, 38.0 mmol) was addeddropwisely therein, and then the reaction was carried out overnight atroom temperature. Next day, sodium borohydride (NaBH₄) (1.4 g, 37.0mmol) was added in batches and the resulting reaction mixture wasreacted for 2 h at 0° C. After the reaction was completed, 20 mL ofwater was added therein to quench the reaction. The solid was removed byfiltration and the filtrate was collected and concentrated. The crudeproduct was purified by Combi-FLASH (Rapid chromatography columnanalyzer) (Column, C18 silica gel; mobile phase: water (0.05%TFA)/CH₃CN=5%-15%, 12 min, detection wavelength: 200 nm). The obtainedproduct was collected, concentrated, and dissolved in 100 mL of water.The resulting product was adjusted to pH 9 with NaHCO₃, and thenextracted with 100 mL of chloroform three times. The organic phases werecombined, washed with 100 mL of saturated solution of NaCl once, driedover anhydrous Na₂SO₄, and concentrated to give 600 mg of theintermediate 059-3 (26%) as colorless oil. LCMS: 125.1.

4. Synthesis of Intermediate 059-5

Sodium hydroxide (NaOH) (580 mg, 14.5 mmol), H₂O (10 mL),dimethylamino-2-chloroethane hydrochloride 005-4 (1.4 g, 9.79 mmol) weresequentially added in a 30 mL single-necked flask, and the reaction wascarried out at room temperature for 5 min. The intermediate 059-3 (600mg, 4.83 mmol) was added at room temperature for 2 h, and the reactionwas carried out for 2h. After the reaction was completed, the reactionwas extracted with 50 mL of chloroform three times. The organic phaseswere combined, and washed with 50 mL of saturated solution of NaCl once,dried over anhydrous Na₂SO₄, and concentrated to give 300 mg as yellowoil. LCMS: 196.2.

5. Synthesis of Intermediate 059-6

The intermediate 059-5 (300 mg, 1.54 mmol), 30 mL of methanol, and Pd/Ccontaining water (1.0 g, 5% Pd) were sequentially added to the 100 mLsingle-necked flask, followed by introducing hydrogen gas. The reactionwas carried out at room temperature for 3 h. After the reaction wascompleted, the palladium on carbon was filtered off and the filtrate wascollected and concentrated to give 100 mg of the intermediate 059-6 asyellow oil. LCMS: 106.2.

6. Synthesis of Compound 59

The reaction steps and conditions for the synthesis of final compound 58and its hydrochloride 58. (HCl)_(n) from the intermediates 040-2 and059-6 were the same as those in the third to fifth steps of example 55,except that the intermediate 055-3 in example 55 was replaced with theintermediate 040-2 and the intermediate 001-10 in example 55 wasreplaced with the intermediate 059-6. Analytical data for thehydrochloride 59.(HCl)_(n): LCMS C₂₇H₂₄D₃N₈O₃: (ES, m/z): 520 [M+H]⁺.¹H-NMR: (DMSO-D₆, 300 MHz, ppm) δ 10.03-10.31 (m, 1H), 9.78-9.87 (s,1H), 9.00-9.21 (m, 1H), 8.43-8.45 (d, J=6 Hz, 1H), 8.17 (br s, 1H),7.78-7.80 (m, 1H), 7.17-7.24 (m, 2H), 6.99-7.09 (m, 3H), 6.19-6.25 (m,1H), 5.69-5.72 (m, 1H), 3.81 (s, 3H), 3.37 (s, 3H), 3.32 (m, 4H), 2.75(s, 3H), 2.76 (s, 3H).

Example 60

1. Synthesis of Intermediate 060-2

The intermediate 060-1 (10 g, 63.7 mmol), 100 mL of anhydrous DMF, K₂CO₃(1.3 g, 9.34 mmol) and deuterated methyl iodide (11 g, 75.9 mmol) weresequentially added to a 250 mL three-necked flask under a nitrogenatmosphere. The reaction was heated to 50° C. and carried out for 2 h inan oil bath. Then, the reaction mixture was cooled to room temperature,quenched with 100 mL of ice water, extracted with 100 mL of EA threetimes, and filtered. The organic phases were washed with 200 mL ofsaturated brine three times, dried over anhydrous sodium sulfate andconcentrated to dryness to give 9.7 g of the intermediate 060-2 (88%) asa yellow solid.

2. Synthesis of Intermediate 060-3

The intermediate 060-2 (9.7 g, 55.7 mmol), 240 mL of methanol andpalladium on carbon (12 g, 5%) were sequentially added to a 500 mLsingle-necked flask, and then the reaction system was replaced byhydrogen gas. After the reaction was carried out at room temperatureovernight, the palladium on carbon was filtered off and the filtrate wasconcentrated to dryness to give 7.2 g of the intermediate 060-3 (90%) asa light-colored liquid. LC-MS: 145.1.

3. Synthesis of Intermediate 060-4

The intermediate 060-3 (7.2 g, 49.9 mmol) and 64 mL of concentratedsulfuric acid were sequentially added to a 250 mL three-necked flaskunder a nitrogen atmosphere. After the reaction was cooled to 0-10° C.,a concentrated nitric acid (HNO₃) (5.05 g, 50.0 mmol) was added inbatches for 15 min. The reaction was carried out at room temperatureovernight. Next, the reaction mixture was added to 500 mL of ice waterto quench the reaction, adjusted to pH 10 with ammonia, extracted with100 mL of EA three times, and washed with 200 mL of saturated brinethree times, dried over anhydrous sodium sulfate and concentrated todryness to give 5.1 g of the intermediate 060-4 (54%) as a yellow solid.LC-MS: 190.1.

4. Synthesis of Compound 60

The reaction steps and conditions for the synthesis of final compound 60and its hydrochloride 60.(HCl)_(n) from the intermediates 040-1 and060-4 were the same as those in the second to fifth steps of example 55,except that the intermediate 055-2 in example 55 was replaced with theintermediate 060-4. Analytical data for the hydrochloride 60.(HCl)_(n):LCMS (parent molecule) C₂₇H₂₉D₃N₈O₃: (ES, m/z): 520.3 [M+H]⁺. ¹H-NMR:(300 MHz, DMSO-D₆, ppm) δ 10.21 (br s, 1H), 9.76 (s, 1H), 9.00-9.03 (m,1H), 8.43-8.47 (d, J=14.4 Hz, 1H), 8.12-8.17 (m, 1H), 7.75-7.77 (d,J=5.7 Hz, 1H), 7.16-7.24 (m, 2H), 6.98-7.06 (m, 3H), 6.19-6.25 (m, 1H),5.69-5.73 (m, 1H), 3.37 (s, 3H), 3.32 (m, 4H), 2.77 (s, 3H), 2.75 (s,3H), 2.73 (s, 3H).

Example 61

1. Synthesis of Compound 61

The reaction steps and conditions for the synthesis of final compound 61and its hydrochloride 61.(HCl)_(n) from the intermediates 039-5 and057-3 were the same as those in the third to fifth steps of example 55,except that the intermediate 055-3 in example 55 was replaced with theintermediate 039-5 and the intermediate 001-10 in example 55 wasreplaced with the intermediate 057-3. Analytical data for thehydrochloride 61.(HCl)_(n): LCMS (parent molecule) C₂₆H₂₄ D₆ N₈O₃: (ES,m/z): 509.3 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ 11.49 (s, 1H),10.33 (br, 1H), 9.81 (s, 1H), 8.40-8.42 (d, J=6 Hz, 1H), 8.18 (s, 1H),8.10 (m, 1H), 7.79-7.81 (d, J=6.3 Hz, 1H), 6.92-7.14 (m, 5H), 6.18-6.24(m, 1H), 5.68-5.72 (m, 1H), 3.96 (s, 3H), 3.32 (m, 4H), 2.64 (s, 3H).

Example 62

1. Synthesis of Compound 62

The reaction steps and conditions for the synthesis of final compound 62and its hydrochloride 62.(HCl) from the intermediates 005-3 and 057-3were the same as those in the third to fifth steps of example 55, exceptthat the intermediate 055-3 in example 55 was replaced with theintermediate 005-3 and the intermediate 001-10 in example 55 wasreplaced with the intermediate 057-3. Analytical data for thehydrochloride 62.(HCl)_(n): LCMS (parent molecule) C₂₇H₂₇ D₆ N₇O₂: (ES,m/z): 494.3 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ 10.50 (br, 1H),9.89-9.96 (m, 2H), 8.04-8.15 (m, 2H), 7.29-7.31 (m, 1H), 7.02-7.20 (m,4H), 6.54 (br s, 1H), 6.16-6.22 (m, 1H), 5.66-5.70 (m, 1H), 4.17-4.23(m, 2H), 3.82 (s, 3H), 3.34 (m, 4H), 3.21-3.26 (m, 2H), 2.66 (s, 3H).

Example 63

1. Synthesis of Compound 63

The reaction steps and conditions for the synthesis of final compound 63and its hydrochloride 63.(HCl)_(n) from the intermediates 004-3 and057-3 were the same as those in the third to fifth steps of example 55,except that the intermediate 055-3 in example 55 was replaced with theintermediate 004-3 and the intermediate 001-10 in example 55 wasreplaced with the intermediate 057-3. Analytical data for thehydrochloride 63.(HCl)_(n): LCMS (parent molecule) C₂₈H₂₇D₆N₇O₂: (ES,m/z): 506 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ 10.37 (br s, 1H),9.84 (s, 1H), 8.44-8.30 (m, 3H), 8.01 (m, 1H), 7.58-7.57 (d, J=2.1 Hz1H), 7.24-7.07 (m, 4H), 7.02 (s, 1H), 6.25-6.19 (dd, J=17.1 Hz, 2.1 Hz,1H), 5.72-5.68 (dd, J=9.9 Hz, 2.1 Hz, 1H), 3.83 (s, 3H), 3.34-3.26 (m,4H), 2.66 (s, 3H), 2.29 (s, 3H).

Example 64

1. Synthesis of Compound 64

The reaction steps and conditions for the synthesis of final compound 64and its hydrochloride 64.(HCl)_(n) from the intermediates 002-3 and057-3 were the same as those in the third to fifth steps of example 55,except that the intermediate 055-3 in example 55 was replaced with theintermediate 002-3 and the intermediate 001-10 in example 55 wasreplaced with the intermediate 057-3. Analytical data for thehydrochloride 64.(HCl)_(n): LCMS (parent molecule) C₂₅H₂₃D₆N₉O₂: (ES,m/z): 494.3 [M+H]⁺. H-NMR: (300 MHz, DMSO-D₆, ppm) δ 10.26 (br, 1H),9.49 (s, 1H), 9.18-9.21 (s, 1H), 8.59-8.61 (d, J=5.7 Hz, 1H), 8.41 (brs, 1H), 8.18-8.24 (m, 2H), 7.62-7.67 (m, 1H), 7.51-7.56 (m, 2H),7.00-7.12 (m, 2H), 6.17-6.23 (m, 1H), 5.68-5.72 (m, 1H), 3.82 (s, 3H),3.31-3.34 (m, 4H), 2.65 (s, 3H).

Example 65

1. Synthesis of Intermediate 065-1

The reaction steps and conditions for the synthesis of final compound 58and its hydrochloride 58.(HCl)_(n) from the intermediates 039-4 and065-1 were the same as those in the first step of example 40, exceptthat iodomethane in example 40 was replaced with deuterated methyliodide (CD₃I). LCMS: 264.1.

2. Synthesis of Compound 65

The reaction steps and conditions for the synthesis of final compound 65and its methanesulfonate 65.(MsOH)₂ from the intermediates 065-1 and006-4 were the same as those in the second to fifth steps of example 40,except that the intermediate 040-1 in example 55 was replaced with theintermediate 065-1. Analytical data for the methanesulfonate 65.(MsOH)₂:LCMS (parent molecule) C₂₇H₂₉ D₃ N₈O₃: (ES, m/z): 520 [M+H]⁺. ¹H-NMR(parent molecule): (300 MHz, DMSO-D₆, ppm) δ 10.09 (s, 1H), 8.73 (s,1H), 8.42-8.44 (m, 2H), 8.09-8.11 (m, 1H), 7.68-7.70 (d, J=5.7 Hz, 1H),7.15-7.20 (m, 2H), 7.05 (s, 1H), 6.87-6.92 (m, 1H), 6.35-6.44 (m, 1H),6.15-6.22 (m, 1H), 5.70-7.74 (m, 1H), 3.75 (s, 3H), 2.89-2.92 (m, 2H),2.75 (s, 3H), 2.32-2.36 (m, 2H), 2.21 (s, 6H). ¹H-NMR(methanesulfonate): (300 MHz, DMSO-D₆, ppm) δ 9.24 (s, 1H), 9.15 (br s,2H), 8.45 (d, J=6.3 Hz, 1H), 8.15-8.11 (m, 2H), 7.84-7.80 (m, 1H),7.26-7.18 (m, 2H), 7.18-6.96 (m, 2H), 6.70-6.61 (m, 1H), 6.30-6.24 (m,1H), 5.80-5.76 (m, 1H), 3.82 (s, 3H), 3.33 (m, 4H), 2.83 (s, 3H), 2.82(s, 3H), 2.51 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H).

Example 66

1. Synthesis of Intermediate 066-1

Under a nitrogen atmosphere, the intermediate 039-4 (3.7 g, 15.0 mmol)as a raw material was dissolved in 150 mL of anhydrous DMF in a 250 mLthree-necked flask. Then, the reaction system was cooled to 0° C., andsodium hydride (540 mg, 22.5 mmol) was sequentially added therein. Thereaction system was kept at 0° C. for 1h, and then adding iodoethane(3.51 g, 22.5 mmol). Next, the reaction was carried out at roomtemperature overnight. After detecting the reaction was completed, thereaction solution was poured into 500 mL of ice water to quench thereaction. The mixture was filtered by suction, and the filter cake wascollected and dried to give 2.8 g of compound 066-1 (68%) as a whitesolid. LCMS: 275.1.

2. Synthesis of Compound 66

The reaction steps and conditions for the synthesis of final compound 66and its methanesulfonate 66.(MsOH)₃ from the intermediates 066-1 and006-4 were the same as those in the second to fifth steps of example 40,except that the intermediate 040-1 in example 40 was replaced with theintermediate 066-1. Analytical data for the compound 66: LCMS (parentmolecule) C₂₈H₃₄N₈O₃: (ES, m/z): 531 [M+H]⁺. ¹H-NMR (parent molecule):(300 MHz, DMSO-D₆, ppm) δ 10.09 (s, 1H), 8.73 (s, 1H), 8.42-8.44 (m,2H), 8.08-8.11 (m, 1H), 7.67-7.69 (d, J=5.7 Hz, 1H), 7.24-7.26 (m, 1H),7.12-7.17 (m, 1H), 7.05 (s, 1H), 6.86-6.91 (m, 1H), 6.35-6.44 (m, 1H),6.15-6.22 (m, 1H), 5.70-5.74 (m, 1H), 3.88-3.95 (m, 2H), 3.75 (s, 3H),2.88-2.92 (m, 2H), 2.75 (s, 3H), 2.34-2.36 (m, 21H), 2.20 (s, 6H),1.21-1.26 (m, 3H). ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm):9.49 (br s, 2H), 9.28 (br s, 1H), 8.46 (d, J=6.3 Hz, 1H), 2.89-2.82 (s,6H), 8.14-8.10 (m, 2H), 7.90 (d, J=6.3 Hz, 1H), 7.33-7.30 (m, 1H),7.25-7.20 (m, 1H), 7.06 (s, 1H), 7.01-6.96 (m, 1H), 6.73-6.64 (m, 1H),6.30-6.18 (m, 1H), 5.87-5.76 (m, 1H), 3.97-3.90 (m, 2H), 3.82 (s, 3H),3.34 (m, 4H), 2.67 (s, 3H), 2.38 (s, 9H), 1.27-1.25 (m, 3H).

Example 67

1. Synthesis of Intermediate 067-2

Under a nitrogen atmosphere, the intermediate 067-1 (1.1 g, 6.36 mmol)as a raw material and 2,4-dichioropyrimidine were dissolved in 80 mL ofa mixed solvent of DME/H₂O (3:1) in a 250 mL three-necked flask at roomtemperature, followed by adding potassium carbonate (2.9 g, 20.8 mmol)and dichlorobis(triphenylphosphine)palladium (470 mg, 0.67 mmol). Thereaction system was heated to 90° C. and carried out overnight. Nextday, after detecting the reaction was completed, and then the reactionsystem was cooled to room temperature. The reaction mixture wasfiltrated by suction, and the filtrate was collected, directlyconcentrated to dryness. The crude product was washed with 30 mL ofanhydrous ether once. The reaction mixture was filtered by suction tocollect the filter cake which was dried to give 1.25 g of theintermediate 067-2 (77%) as a brown solid. LCMS: 242.0.

2. Synthesis of Compound 67

The reaction steps and conditions for the synthesis of final compound 67from the intermediates 067-2 and 006-4 were the same as those in thesecond to fifth steps of example 40, except that the intermediate 040-1in example 40 was replaced with the intermediate 067-2. Analytical datafor the compound 67: LCMS (parent molecule): C₂H₃₁D₆N₇O₂: (ES, m/z): 498[M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm) δ 10.04 (s, 1H), 9.41 (s, 1H),8.71 (s, 1H), 8.65 (s, 1H), 8.58-8.57 (d, J=4.8 Hz, 1H), 8.49 (s, 1H),8.45-8.35 (m, 1H), 8.20 (m, 1H), 7.85-7.70 (m, 1H), 7.16 (d, J=4.8 Hz,1H), 7.00 (s, 1H), 6.45-6.30 (m, 1H), 6.20-6.15 (m, 1H), 5.80-5.70 (m,1H), 3.82 (s, 3H), 2.84 (m, 2H), 2.70 (s, 3H), 2.28 (m, 2H), 2.18 (s,3H).

Example 68

The reaction steps and conditions for the synthesis of final compound 68and its methanesulfonate were the same as those in the third to fifthsteps of example 40, except that the intermediate 040-2 in example 40was replaced with the intermediate 066-2 and the intermediate 001-10 inexample 40 was replaced with the intermediate 059-6.

Analytical data for the compound 68: LCMS (parent molecule)C₂₈H₃₁D₃N₈O₃: (ES, m/z): 534.3 [M+H]⁺. ¹H-NMR (methanesulfonate): (300MHz, DMSO-D₆, ppm): δ 9.51 (s, 1H), 9.12 (br s, 2H), 8.45 (d, J=6 Hz,1H), 8.15-8.10 (m, 2H), 7.80 (d, J=5.7 Hz, 1H), 7.31-7.23 (m, 1H),7.20-7.18 (m, 1H), 7.04-6.95 (m, 2H), 6.70-6.61 (m, 1H), 6.30-6.25 (m,1H), 5.80-5.76 (m, 1H), 3.97-3.90 (m, 2H), 3.82 (s, 3H), 3.32 (m, 4H),2.83 (s, 3H), 2.82 (s, 3H), 2.35 (s, 6H), 1.27-1.22 (m, 3H).

Example 69

The reaction steps and conditions for the synthesis of final compound 69and its methanesulfonate were the same as those in the third to fifthsteps of example 40, except that the intermediate 040-2 in example 40was replaced with the intermediate 066-2 and the intermediate 001-10 inexample 40 was replaced with the intermediate 057-3.

Analytical data for the compound 69: LCMS (parent molecule)C₂₈H₂₈D₆N₈O₃: (ES, m/z): 537.3[M+H]⁺. ¹H-NMR (methanesulfonate): (300MHz, DMSO-D₆, ppm): δ 9.54 (s, 1H), 9.22 (br s, 1H), 8.87 (br s, 1H),8.46-8.44 (m, 1H), 8.18-8.11 (m, 2H), 7.75-7.73 (m, 1H), 7.30-7.28 (m,1H), 7.21-7.16 (m, 1H), 7.02-6.95 (m, 2H), 6.69-6.60 (m, 1H), 6.31-6.25(m, 1H), 5.80-5.76 (m, 1H), 3.95-3.82 (m, 2H), 3.32-3.29 (m, 4H), 2.51(s, 3H), 2.30 (s, 9H), 1.27-1.22 (m, 3H).

Example 70

The reaction steps and conditions for the synthesis of final compound 70and its methanesulfonate were the same as those in the third to fifthsteps of example 40, except that the intermediate 040-2 in example 40was replaced with the intermediate 049-2 and the intermediate 001-10 inexample 40 was replaced with the intermediate 057-3.

Analytical data for the compound 70: LCMS (parent molecule)C₂₈H₂₇D₆N₇O₄S: (ES, m/z): 570.3 [M+H]⁺. ¹H-NMR (methanesulfonate): (300MHz, DMSO-D₆, ppm): δ 9.56 (s, 1H), 9.26 (br s, 1H), 8.65 (s, 1H),8.48-8.41 (m, 2H), 8.33 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.57 (d, J=5.4Hz, 1H), 7.47-7.42 (m, 2H), 7.35-7.27 (m, 1H), 7.05 (s, 1H), 6.71-6.61(m, 1H), 6.31-6.26 (m, 1H), 5.81-5.77 (m, 1H), 3.87 (s, 3H), 3.61 (s,3H), 3.30-3.32 (m, 4H), 2.66 (s, 3H), 2.34 (s, 6H).

Example 71

The reaction steps and conditions for the synthesis of final compound 71and its methanesulfonate were the same as those in the third to fifthsteps of example 40, except that the intermediate 040-2 in example 40was replaced with the intermediate 049-2 and the intermediate 001-10 inexample 40 was replaced with the intermediate 059-6.

Analytical data for the compound 71: LCMS (parent molecule)C₂₈H₃D₃N₇O₄S: (ES, n/z): 567.3[M+H]⁺. ¹H-NMR (methanesulfonate): (300MHz, DMSO-D₆, ppm): δ 9.56 (s, 1H), 9.29 (br s, 1H), 8.69 (s, 1H),8.47-8.41 (m, 2H), 8.30 (s, 1H), 8.15-8.11 (m, 2H), 7.91 (d, J=8.4 Hz,1H), 7.60 (d, J=5.7 Hz, 1H), 7.47-7.42 (m, 1H), 7.34-7.29 (m, 1H), 7.05(s, 1H), 7.18-6.96 (m, 2H), 6.72-6.63 (m, 1H), 6.31-6.25 (m, 1H),5.80-5.77 (m, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 3.32 (m, 4H), 2.83 (s,3H), 2.82 (s, 3H), 2.35 (s, 3H).

Example 72

The reaction steps and conditions for the synthesis of final compound 72and its methanesulfonate were the same as those in the third to fifthsteps of example 40, except that the intermediate 040-2 in example 40was replaced with the intermediate 048-4 and the intermediate 001-10 inexample 40 was replaced with the intermediate 057-3.

Analytical data for the compound 72: LCMS (parent molecule)C₂₉H₂₉D₆N₇O₂: (ES, m/z): 520.3[M+H]⁺. ¹H-NMR (methanesulfonate): (300MHz, DMSO-D₆, ppm): δ 9.52 (s, 1H), 9.25 (br s, 1H), 8.81 (s, 1H),8.43-8.42 (br s, 1H), 8.27-8.25 (m, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.42(d, J=6.3 Hz, 1H), 7.31-7.26 (m, 1H), 7.19-7.14 (m, 1H), 7.08 (s, 1H),6.77-6.68 (m, 1H), 6.32-6.25 (m, 1H), 5.81-5.77 (m, 1H), 4.38-4.24 (m,2H), 3.87 (s, 3H), 3.33 (m, 4H), 2.67 (s, 3H), 2.32 (s, 9H), 1.48-1.43(m, 3H).

Example 73

The reaction steps and conditions for the synthesis of final compound 73and its methanesulfonate were the same as those in the third to fifthsteps of example 40, except that the intermediate 040-2 in example 40was replaced with the intermediate 048-4 and the intermediate 001-10 inexample 40 was replaced with the intermediate 059-6.

Analytical data for the compound 72: LCMS (parent molecule)C₂₉H₃₂D₃N₇O₂: (ES, m/z): 517.3[M+H]⁺. ¹H-NMR (methanesulfonate): (300MHz, DMSO-D₆, ppm): δ 9.51 (s, 1H), 9.33 (br s, 1H), 8.85 (s, 1H),8.36-8.24 (br s, 3H), 7.67-7.64 (m, 2H), 7.47-7.44 (m, 1H), 7.26-7.18(m, 2H), 7.18-6.96 (m, 2H), 6.70-6.61 (m, 1H), 6.31-6.25 (m, 1H),5.81-5.77 (m, 1H), 4.38-4.25 (m, 2H), 3.86 (s, 3H), 3.37-3.33 (m, 4H),2.85 (s, 3H), 2.84 (s, 3H), 2.36 (s, 6H), 1.49-1.44 (m, 3H).

Example 74

The reaction steps and conditions for the synthesis of final compound 74and its methanesulfonate were the same as those in the third to fifthsteps of example 40, except that the intermediate 040-2 in example 40was replaced with the intermediate 040-2 and the intermediate 001-10 inexample 40 was replaced with the intermediate 059-6.

Analytical data for the compound 74: LCMS (parent molecule) C₂₉H₃₂D₃N₇₂:(ES, m/z): 491.3[M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆,ppm): δ 9.55 (s, 1H), 9.25 (br s, 2H), 8.60-8.62 (m, 1H), 8.45 (br s,1H), 8.16-8.23 (m, 2H), 7.52-7.66 (m, 3H), 7.05 (s, 1H), 6.59-6.73 (m,1H), 6.24-6.30 (m, 1H), 5.76-5.80 (m, 1H), 3.83 (s, 3H), 3.34 (m, 4H),2.84 (s, 3H), 2.83 (s, 3H), 2.38 (s, 9H).

Example 76

The reaction steps and conditions for the synthesis of final compound 76and its methanesulfonate were the same as those in the third to fifthsteps of example 40, except that the intermediate 040-2 in example 40was replaced with the intermediate 065-2 and the intermediate 001-10 inexample 40 was replaced with the intermediate 059-6.

Analytical data for the compound 76: LCMS (parent molecule) C₂₇H₂₆D₆N₈O₃: (ES, m/z): 523.5 [M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz,DMSO-D₆, ppm): δ 9.51 (s, 1H), 9.24-9.25 (br s, 2H), 8.44 (d, J=5.7 Hz,1H), 8.10-8.15 (m, 2H), 7.81 (d, J=5.7 Hz, 1H), 7.18-7.25 (m, 2H),6.98-7.04 (m, 2H), 6.61-6.70 (m, 1H), 6.24-6.30 (m, 1H), 5.76-5.79 (m,1H), 3.82 (s, 3H), 3.32 (m, 4H), 2.83 (s, 3H), 2.81 (s, 3H), 2.34 (s,6H).

Example 101

1. Synthesis of Intermediate 101-1

Under a nitrogen atmosphere, the intermediate 048-2 (1.5 g, 6.53 mmol)as a raw material was dissolved in 20 mL of anhydrous DMF in a 100 mLthree-necked flask at room temperature. The reaction was cooled to 0° C.and sodium hydride (393 mg, 9.82 mmol) was added thereto in batches.Next, the reaction was carried out at 0° C. for 0.5 h, ethylsulfonylchloride (1.08 g, 8.41 mmol) was added into the reaction system at 0°C., and then the reaction was carried out at room temperature for 2h.After detecting the reaction was completed, the reaction mixture waspoured into 10 ML of ice water to quench the reaction. The resultingmixture was extracted twice with 100 mL of ethyl acetate (EA). Theorganic phases were collected and washed twice with 100 mL of brine. Theorganic phases were dried over anhydrous sodium sulfate and concentratedto dryness. The resulting residue was purified with silica gel columnchromatography (eluent: petroleum ether (PE): ethyl acetate (EA)=10:1).The product was collected and concentrated to give 2.0 g of theintermediate 101-1 (95%) as a red solid. LCMS: 322.

2. Synthesis of Intermediate 101-2

Under a nitrogen atmosphere, 20 mL of isopropyl alcohol, theintermediate 101-1 (2.0 g, 6.22 mmol), the intermediate 001-1 (1.15 g,6.18 mmol) and p-toluenesulfonic acid (1.39 g, 8.07 mmol) weresequentially added into a 100 mL single-necked flask at roomtemperature. Next, the reaction was heated to 105° C. and carried outfor 2 h. After detecting the reaction was completed, the reaction systemwas cooled to room temperature and quenched by adding 100 mL of icewater. The reaction mixture was filtered, and the solid was collectedand dried to give 2.1 g of the intermediate 101-2 as a red solid. LCMS:472.

3. Synthesis of Intermediate 101-3

Under a nitrogen atmosphere, the intermediate 101-2 (2.1 g, 4.45 mmol)as a raw material was dissolved in 20 mL of NMP at room temperature in a100 mL single-necked flask, followed by sequentially addingN,N,N′-trimethylethylenediamine (682 mg, 6.67 mmol) and anhydrouspotassium carbonate (1.85 g, 13.4 mmol) into the reaction system. Next,the reaction system was heated to 30° C., and then carried out for 24h.After detecting the reaction was completed, the reaction system wascooled to room temperature. The reaction mixture was poured into 200 mLof ice water to quench the reaction. A solid was precipitated and thereaction mixture was filtered under suction. The solid was collected anddried to give 2 g of the intermediate 101-3 as a red solid. LCMS: 554.

4. Synthesis of Intermediate 101-4

Under a nitrogen atmosphere, 30 mL of ethanol, 10 mL of water, theintermediate 101-3 (2.0 g, 3.36 mmol) as a raw material, iron powder(1.21 g, 21.61 mmol) and ammonium chloride (134 mL, 2.51 mmol) weresequentially added into a 100 mL single-necked flask at roomtemperature, followed by that the reaction was heated to 85° C. andcarried out for 3 h. After detecting the reaction was completed, thereaction was cooled to room temperature. The resulting mixture wasfiltered by suction, and the filtrate was collected and concentrated todryness. The resulting residue was purified by preparative HPLC (column:C18 silica gel; mobile phase: acetonitrile/water (0.05% trifluoroaceticacid); 35% acetonitrile to 50% acetonitrile; 15 min; 70 mL/min;detection wavelength: 254 nm). The product was collected, and thecombined mixture was adjusted with a saturated solution of sodiumbicarbonate to pH=8, extracted three times with 200 mL of methylenechloride. The organic was collected, combined, dried over anhydroussodium sulfate and concentrated to dryness to give 1.3 g of theintermediate 101-4 (69%) as a green solid. LCMS: 524.

5. Synthesis of Compound 101

Under a nitrogen atmosphere, the intermediate 101-4 (400 mg, 0.76 mmol)as a raw material was dissolved in 10 mL of chloroform at roomtemperature in a 50 mL single-necked flask and acrylic anhydride (125mg, 0.99 mmol) was added to the reaction system. Next, the reaction wascarried out at room temperature for 2h. After detecting the reaction wascompleted, the reaction system was quenched with 2 mL of ice water andconcentrated to dryness. The resulting residue was purified by highpressure HPLC (column; Waters X-bridge C18, 19*150 mm; the mobile phase:water (0.05% ammonia)/acetonitrile, 40% acetonitrile to 85%acetonitrile, 9 mini, 15 mL/min; detection wavelength: 254 nm). Theproduct was collected and concentrated to dryness to give compound 101.

The compound 101 was dissolved in 2 mL of acetonitrile, methanesulfonicacid (2.0 eq) was added thereto and the reaction mixture was freezedried to give 73.8 mg of methanesulfonate of the compound 101 (13%) as ayellow solid. LCMS (parent molecule) C₂₉H₃₅S N₇O₄: (ES, m/z): 578[M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm): δ 9.56 (s,1H), 9.25 (br s, 1H), 8.65 (s, 1H), 8.48-8.41 (m, 2H), 8.31 (s, 1H),7.91 (d, J=8.1 Hz, 1H), 7.59 (d, J=5.1 Hz, 1H), 7.47-7.42 (m, 2H), 7.05(s, 1H), 6.71-6.61 (m, 1H), 6.326-6.26 (m, 1H), 5.81-5.77 (m, 1H),3.85-3.81 (s, 3H), 3.78-3.73 (s, 2H), 3.32 (m, 4H), 2.83-2.82 (s, 6H),2.65 (s, 3H), 2.27-2.50 (s, 6H), 1.08-1.23 (m, 3H).

Example 102

1. Synthesis of Intermediate 102-1

The reaction steps and conditions for the synthesis of compound 102-1were the same as those in the first step of example 101, except thatethylsulfonyl chloride in example 101 was replaced withisopropylsulfonyl chloride. LCMS: 336.

2. Synthesis of Intermediate 102-2

Under a nitrogen atmosphere, 20 mL of isopropyl alcohol, theintermediate 102-1 (2.0 g, 6.55 mmol), the intermediate 006-4 (1.2 g,6.45 mmol) and p-toluenesulfonic acid (1.47 g, 8.52 mmol) weresequentially added into a 100 mL single-necked flask at roomtemperature. Next, the reaction was heated to 105° C. and carried outfor 2 h. After detecting the reaction was completed, the reaction systemwas cooled to room temperature and quenched by adding 100 mL of icewater. The reaction mixture was filtered, and the solid was collectedand dried to give 2.1 g of the intermediate 102-2 as a red solid. LCMS:486.

3. Synthesis of Intermediate 102-3

Under a nitrogen atmosphere, the intermediate 102-3 (2.1 g, 4.33 mmol)as a raw material was dissolved in 20 mL of NMP at room temperature in a100 mL single-necked flask, followed by sequentially addingN,N,N′-trimethylethylenediamine (662 mg, 6.48 mmol) and anhydrouspotassium carbonate (1.85 g, 13.82 mmol) into the reaction system. Next,the reaction system was heated to 30° C., and then carried out for 24h.After detecting the reaction was completed, the reaction system wascooled to room temperature. The reaction mixture was poured into 200 mLof ice water to quench the reaction. The reaction mixture was filteredand the solid was collected and dried to give 2 g of the intermediate102-3 (81%) as a red solid. LCMS: 568.

4. Synthesis of Intermediate 1024

Under a nitrogen atmosphere, 30 mL of ethanol, 10 mL of water, theintermediate 102-3 (2.0 g, 3.52 mmol) as a raw material, iron powder(1.18 g, 21.1 mmol) and ammonium chloride (143 mL, 2.67 mmol) weresequentially added into a 100 mL single-necked flask at roomtemperature, followed by that the reaction was heated to 85° C. andcarried out for 3 h. After detecting the reaction was completed, thereaction was cooled to room temperature. The resulting mixture wasfiltered by suction, and the filtrate was collected and concentrated todryness. The resulting residue was purified by Comi-Flash-HPLC (column:C18 silica gel; mobile phase: acetonitrile/water (0.05% trifluoroaceticacid); 35% acetonitrile to 50% acetonitrile; 15 min; 70 mL/min;detection wavelength: 254 nm). The product was collected, and thecombined mixture was adjusted with a saturated solution of sodiumbicarbonate to pH=8, extracted three times with 200 mL of methylenechloride. The organic was collected, combined, dried over anhydroussodium sulfate and concentrated to dryness to give 1.1 g of theintermediate 102-4 (58%) as a green solid. LCMS: 538.

5. Synthesis of Compound 102

Under a nitrogen atmosphere, the intermediate 102-4 (400 mg, 0.74 mmol)as a raw material was dissolved in 10 mL of chloroform at roomtemperature in a 50 mL single-necked flask and acrylic anhydride (122mg, 0.97 mmol) was added to the reaction system. Next, the reaction wascarried out at room temperature for 2h. After detecting the reaction wascompleted, the reaction system was quenched with 2 mL of ice water andconcentrated to dryness. The resulting residue was purified by highpressure HPLC (column: Waters X-bridge C18, 19*150 mm; the mobile phase:0.05% ammonia/acetonitrile, 40% acetonitrile to 85% acetonitrile, 9 min,15 mL/min; detection wavelength: 254 nm). The product was collected andconcentrated to dryness to give compound 102.

The compound 102 was dissolved in 2 mL of acetonitrile, methanesulfonicacid (2.0 eq) was added thereto and the reaction mixture was freezedried to give 25.7 mg of methanesulfonate of the compound 102 (4%) as ayellow solid. LCMS (parent molecule) C₃₀H₃₇S N₇O₄: (ES, m/z): 592[M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm): δ9.56 (s,1H), 9.25 (br s, 1), 8.65 (s, 1H), 8.48-8.41 (m, 2H), 8.31 (s, 1H), 7.91(d, J=8.1 Hz, 1H), 7.59 (d, J=5.1 Hz, 1H), 7.47-7.42 (m, 2H), 7.05 (s,1H), 6.71-6.61 (m, 1H), 6.32-6.26 (m, 1H), 5.81-5.77 (m, 1H), 3.95-3.86(m, 4H), 3.32 (m, 4H), 2.83-2.82 (s, 6H), 2.65 (s, 3H), 2.34-2.21 (s,6H), 1.26-1.12 (m, 6H).

Example 103

1. Synthesis of Compound 103

The reaction steps and conditions for the synthesis of compound 103 andits methanesulfonate were the same as those in the first to fifth stepsof example 102, except that isopropylsulfonyl chloride in example 102was replaced with the intermediate of cyclopropylsulfonyl chloride inthe first step. LCMS (parent molecule) C₃₀H₃₇SN₇O₄: (ES, m/z): 590[M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm): δ 9.56 (s,1H). 9.25 (br s, 1H), 8.72 (s, 1H), 8.43-8.41 (m, 2H), 8.31 (s, 1H),7.96 (d, J=8.4 Hz, 1H), 7.61 (d, J=4.8 Hz, 1H), 7.47-7.31 (m, 2H), 7.05(s, 1H), 6.72-6.63 (m, 1H), 6.28 (d, J=16.5 Hz, 1H), 5.78 (d, J=10.2 Hz,1H), 3.86 (s, 3H), 3.41-3.20 (m, 5H), 2.82 (s, 6H), 2.66 (s, 3H), 2.18(s, 6H), 1.36-1.23 (m, 2H), 1.16-1.05 (m, 2H).

Example 104

1. Synthesis of Intermediate 104-2

Under a nitrogen atmosphere, the intermediate 048-2 (3.0 g, 13 mmol) asa raw material was dissolved in 30 mL of N,N-dimethylformamide in a 100mL three-necked flask at room temperature. The reaction system wascooled to 0° C. and sodium hydride (785 mg, 18.5 mmol) was added theretoin batches. Next, the reaction was carried out at 0° C. for 0.5h,trifluoroethyltriflate 104-1 (3.65 g, 15 mmol) was added into thereaction system, followed by that the reaction was carried out at roomtemperature for 2h. After detecting the reaction was completed, thereaction mixture was poured into 200 mL of ice water to quench thereaction. A red solid was precipitated, and the resulting mixture wasfiltrated, and the solid was collected and dried to dryness, to give 4.2g of the intermediate 104-2 as a red solid. LCMS: 312.0.

2. Synthesis of Compound 104

The reaction steps and conditions for the synthesis of compound 104 andits methanesulfonate were the same as those in the second to fifth stepsof example 101, except that the intermediate 101-1 in example 101 wasreplaced with the intermediate 104-2. LCMS (parent molecule)C₂₉H₃₂F₃N₇O₂: (ES, m/z): 568 [M+H]⁺. ¹H-NMR (methanesulfonate): (300MHz, DMSO-D₆, ppm): δ9.51 (s, 1H), 9.35-9.27 (br s, 2H), 8.76 (s, 1H),8.45-8.30 (m, 3H), 7.78 (d, J=8.1 Hz, 1H), 7.44 (d, J=6.3 Hz, 1H),7.36-7.31 (m, 1H), 7.23-7.21 (m, 1H), 7.08 (s, 1H), 6.76-6.67 (m, 1H),6.29 (d, J=16.8 Hz, 1H), 5.80 (d, J=10.8 Hz, 1H), 5.42-5.33 (m, 2H),3.87 (s, 3H), 3.50-3.33 (m, 4H), 2.83 (s, 6H), 2.68 (s, 3H), 2.50 (s,6H).

Example 105

1. Synthesis of Intermediate 105-2

Under a nitrogen atmosphere, the intermediate 048-2 (4.0 g, 17.4 mmol)as a raw material was dissolved in 40 mL of N,N-dimethylformamide in a100 mL three-necked flask at room temperature. The reaction system wascooled to 0° C. and sodium hydride (900 mg, 37.5 mmol) was added theretoin batches. Next, the reaction was carried out at 0° C. for 0.5h, and1,1-difluoro-2-bromoethane (4.8 g, 33.5 mmol) was added into thereaction system, followed by that the reaction was carried out at roomtemperature for 2h. After detecting the reaction was completed, thereaction mixture was poured into 100 mL of ice water to quench thereaction. The resulting mixture was extracted twice with 100 mL of EAand the organic phases were combined and dried to dryness. The resultingresidue was purified by silica gel column chromatography (the usedeluent (PE:EA=10:1-5:1)), and the product was collected and concentratedto dryness so as to give 1.6 g of the intermediate 105-2 (31%) as a redsolid. LCMS: 294.0.

2. Synthesis of Compound 105

The reaction steps and conditions for the synthesis of compound 105 andits methanesulfonate were the same as those in the second to fifth stepsof example 101, except that the intermediate 101-1 in example 101 wasreplaced with the intermediate 105-2. LCMS (parent molecule)C₂₉H₃₃F₂N₇O₂: (ES, m/z): 550 [M+H]⁺. ¹H-NMR (methanesulfonate): (300MHz, DMSO-D₆, ppm): δ9.51 (s, 1H), 9.30 (br s, 2H), 8.77 (s, 1H),8.37-8.29 (m, 3H), 7.71 (d, J=8.1 Hz, 1H), 7.45-7.43 (m, 1H), 7.33-7.26(m, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.09 (s, 1H), 6.77-6.71 (m, 1H), 6.50(s, 1H), 6.28 (d, J=17.4 Hz, 1H), 5.79 (d, J=10.5 Hz, 1H), 4.92-4.81 (m,2H), 3.94 (s, 3H), 3.34-3.31 (m, 4H), 2.83 (s, 6H), 2.68 (s, 3H), 2.50(s, 6H).

Example 106

1. Synthesis of Intermediate 106-1

Under a nitrogen atmosphere, the intermediate 039-4 (5.0 g, 20.3 mmol)as a raw material was dissolved in 100 mL of anhydrous DMF in a 250 mLsingle-necked flask at room temperature. The reaction was cooled to 0°C., and sodium hydride (731 mg, 30.5 mmol) was added thereto in batchesfor 10 min. Next, the reaction was carried out at 0° C. for 1h, and theniodoisopropane (5.18 g, 30.5 mmol) was added into the reaction system,and then the reaction was carried out at room temperature for overnight.After detecting the reaction was completed, the reaction system wasquenched with 400 mL of ice water. The resulting mixture was extractedthree times with 200 mL of dichloromethane. The organic phases werecombined and washed three times with 600 mL of saturated brine. Theorganic phases were dried over anhydrous sodium sulfate and concentratedto dryness. The resulting residue was purified with silica gel columnchromatography (eluent: EA/PE=1:10-1:5). The product was collected andconcentrated to dryness so as to give 3.0 g of the intermediate 106-1(51%) as a white solid. LCMS: 289.1.

2. Synthesis of Intermediate 106-2

Under a nitrogen atmosphere, the intermediate 106-1 (1.5 g, 5.2 mmol) asa raw material was dissolved in 20 mL of isopropyl alcohol in a 100 mLsingle-necked flask at room temperature, then sequentially adding theintermediate 006-4 (969 mg, 5.20 mmol)) and p-toluenesulfonic acid (1.08g, 6.24 mmol) into the reaction system. Next, the reaction was heated to105° C. and carried out overnight. After detecting the reaction wascompleted, the reaction system was cooled to room temperature. Thereaction mixture was filtered, and the filter cake was collected andrinsed three times with 10 mL of isopropanol. The resulting solid wasdried to give 1.3 g of the intermediate 106-2 (57%) as a yellow solid.LCMS: 439.1.

3. Synthesis of Intermediate 106-3

Under a nitrogen atmosphere, the intermediate 106-2 (1.3 g, 2.97 mmol)as a raw material was dissolved in 10 mL of NMP at room temperature in a100 mL single-necked flask, followed by sequentially addingN,N,N′-trimethylethylenediamine (454 mg, 4.44 mmol) and anhydrouspotassium carbonate (1.23 g, 8.82 mmol) into the reaction system. Next,the reaction system was heated to 100° C., and then carried out for 3h.After detecting the reaction was completed, the reaction system wascooled to room temperature. The reaction mixture was poured into 500 mLof ice water to quench the reaction. The reaction mixture was filteredand the filter cake was collected and dried to give 1.4 g of theintermediate 106-3 (91%) as a red solid. LCMS: 521.3.

4. Synthesis of Intermediate 106-4

Under a nitrogen atmosphere, 210 mL of ethanol, 70 mL of water, theintermediate 106-3 (1.4 g, 2.69 mmol) as a raw material, iron powder(905 mg, 16.2 mmol) and ammonium chloride (99.8 mL, 1.87 mmol) weresequentially added into a 500 mL single-necked flask at roomtemperature, followed by that the reaction was heated to 85° C. andcarried out overnight. After detecting the reaction was completed, thereaction was cooled to room temperature. The resulting mixture wasfiltered by suction, and the filtrate was collected and concentrated todryness. The resulting residue was purified by preparativeCombi-Flash-HPLC (column: C18 silica gel; mobile phase:acetonitrile/water (0.05% trifluoroacetic acid); 35% acetonitrile to 50%acetonitrile; 15 min; 70 mL/min; detection wavelength: 254 nm). Theresulting organic phases were concentrated to dryness, so as to give 1.1g of the intermediate 106-4 (68%) as a yellow solid. LCMS: 521.3.

5. Synthesis of Compound 106

Under a nitrogen atmosphere, the intermediate 106-4 (604 mg, 1.00 mmol)as a raw material was dissolved in 10 mL of anhydrous tetrahydrofuran ina 100 mL three-necked flask at room temperature, followed by addingDIPEA (387 mg, 2.99 mmol). The reaction system was cooled to 0° C. andacryloyl chloride (90 mg, 0.99 mmol) was added thereto at 0° C. Next,the reaction was carried out at room temperature for 1h. After detectingthe reaction was completed, the reaction system was quenched with 50 mLof ice water. The resulting mixture was extracted three times with 100mL of dichloromethane. The organic phases were combined, washed threetimes with 300 mL of saturated brine, and dried over anhydrous sodiumsulfate and concentrated to dryness. The resulting residue was purifiedby high pressure preparative Prep-HPLC (column: Waters X-bridge RP18,19*150 mm, 5 um; mobile phase: water (10 mM NH₄HCO₃+0.05% NH₃⁻H₂O)/acetonitrile, 60% acetonitrile to 75% acetonitrile, 8 min, 20mL/min; detection wavelength: 254 nm). The resulting organic phases wereconcentrated to dryness to give the compound 106.

The compound 106 was dissolved in 10 mL of acetonitrile, methanesulfonicacid (2.0 eq) was added thereto and the resulting reaction mixture wasfreeze dried to give 85.0 mg of methanesulfonate of the compound 106(12%) as a yellow solid. LCMS (parent molecule) C₂₉H₃₆N₈O₃: (ES, m/z):545.3 [M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm): δ 9.50(br s, 2H), 9.30 (br s, 1H), 8.45 (d, J=6.3 Hz, 1H), 8.14 (br s, 1H),8.10 (s, 1H), 7.85 (d, J=6.3 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.21-7.16(m, 1H), 7.00-6.95 (m, 1H), 6.74-6.65 (m, 1H), 6.30-6.24 (m, 1H),5.87-5.76 (m, 1H), 4.73-4.64 (m, 1H), 3.83 (s, 3H), 3.33 (m, 4H), 2.83(s, 3H), 2.82 (s, 3H), 2.73 (s, 3H), 2.38 (s, 6H), 1.50 (s, 3H), 1.48(s, 3H).

Example 107

1. Synthesis of Intermediate 107-1

Under a nitrogen atmosphere, o-nitrofluorobenzene (15 g, 106 mmol) as araw material was dissolved in 150 mL of NMP in a 500 mL single-neckedflask at room temperature, followed by sequentially addingcyclopropylamine (9.10 g, 159 mmol), anhydrous potassium carbonate (44g, 316 mmol) the reaction system. Next, the reaction was heated to 100°C. and carried out for 3 h. After detecting the reaction was completed,the reaction system was cooled to room temperature and the reactionmixture was poured into 150 mL ice water to quench the reaction. Thereaction system was extracted three times with 150 mL ofdichloromethane. The organic phases were combined, washed with 500 mL ofsaturated brine three times and dried over anhydrous sodium sulfate andconcentrated to dryness to give 16 g of the intermediate 107-1 (84%) asa yellow oil. LCMS: 179.1.

2. Synthesis of Intermediate 107-2

Under a nitrogen atmosphere, the intermediate 107-1 (16 g, 89.8 mmol) asa raw material was dissolved in 160 mL of anhydrous methanol in a 500 mLsingle-necked flask at room temperature, and then Pd/C (16 g, 5% byweight) and ammonium formate (16 g, 254 mmol) were sequentially added tothe reaction system, then the reaction was carried out at roomtemperature overnight. Next, after detecting the reaction was completed,the reaction mixture was filtered and the filtrate was collected andconcentrated to dryness. The resulting residue was purified by silicagel column chromatography (eluent: EA/PE (1:10-1:5)), and the productwas collected and concentrated to dryness to give 12 g of theintermediate 107-2 (90%) as a colorless oil. LCMS: 149.1.

3. Synthesis of Intermediate 107-3

Under a nitrogen atmosphere, the intermediate 107-2 (8.0 g, 54.0 mmol)as a raw material was dissolved in 100 mL of anhydrous tetrahydrofuranat room temperature in a 250 mL single-necked flask, followed bysequentially adding carbonyldiimidazole CDI (19.7 g, 108 mmol) andpyridine (8.54 g, 108 mmol) into the reaction system. Next, the reactionsystem was heated to 65° C., and then carried out for 3h. Afterdetecting the reaction was completed, the reaction system was cooled toroom temperature. The reaction mixture was poured into 100 mL of icewater to quench the reaction. The reaction system was washed with 300 mLof dichloromethane three times, and the organic phases were combined,washed with 300 mL of saturated brine three times, dried over anhydroussodium sulfate and concentrated to dryness. The resulting residue waspurified by silica gel column chromatography (eluent: EA/PE (1:10-1:5)),and the product was collected and concentrated to dryness to give 4.2 gof the intermediate 107-3 (45%) as a white solid. LCMS: 175.1.

4. Synthesis of Intermediate 107-4

Under a nitrogen atmosphere, the intermediate 107-3 (4.2 g, 24.1 mmol)as a raw material was dissolved in 50 mL of anhydrous DMF in 250 mL of athree-necked flask, then the reaction was cooled to 0° C. and NaH (869mg, 36.2 mmol) was added in batches for 10 min. Next, the reaction wascarried out at 0° C. for 1h, and then 2,4-dichloropyrimidine (5.36 g,36.0 mmol) was added and the reaction was carried out at roomtemperature overnight. Next day, after detecting the reaction wascompleted, the reaction system was quenched with 100 ML of ice water.The system was extracted with 100 mL of methylene chloride three times.The organic phases were combined, washed with 300 mL of saturated brinethree times, dried over anhydrous sodium sulfate and concentrated todryness. The resulting residue was purified by silica gel columnchromatography (eluent: EA/PE=1: 10-1:5) and the product was collectedand concentrated to dryness to give 4 g of the intermediate 107-4 (58%)as a white solid. LCMS: 287.1.

5. Synthesis of Compound 107

The reaction steps and conditions for the synthesis of compound 107 andits methanesulfonate from the intermediate 107-4 were the same as thosein the second to fifth steps of example 101, except that theintermediate 101-1 in example 101 was replaced with the intermediate107-4. Data for compound 107: LCMS (parent molecule) C₂₉H₃₄N₈O₃: (ES,m/z): 543.3[M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm): δ9.49-9.26 (m, 3H), 8.44 (d, J=6.3 Hz, 1H), 8.10 (br s, 2H), 7.83-7.81(m, 1H), 7.31-7.19 (m, 2H), 7.05-6.96 (m, 2H), 6.72-6.64 (m, 1H),6.29-6.24 (m, 1H), 5.79-5.76 (m, 1H), 3.82 (s, 3H), 3.33 (m, 4H),2.95-2.93 (m, 1H), 2.83 (s, 3H), 2.82 (s, 3H), 2.66 (s, 3H), 2.37 (s,6H), 1.10-1.08 (m, 2H), 0.93 (m, 2H).

Example 108

1. Synthesis of Intermediate 108-1

Under a nitrogen atmosphere, the intermediate 039-4 (3.0 g, 12 mmol) asa raw material was dissolved in 30 mL of N,N-dimethylformamide in a 100mL three-necked flask at room temperature. The reaction system wascooled to 0° C. and sodium hydride (731 mg, 18.2 mmol) was added theretoin batches. Next, the reaction was carried out at 0° C. for 0.5h,trifluoroethylmethanesulfonate (3.39 g, 14.6 mmol) was added into thereaction system, then the reaction was carried out at room temperaturefor 2h. After detecting the reaction was completed, the reaction mixturewas poured into 200 mL of ice water to quench the reaction. A red solidwas precipitated, and the resulting mixture was filtrated, and the solidwas collected and dried to dryness to give 3.5 g of the intermediate108-1 as a red solid. LCMS: 329.0.

2. Synthesis of Compound 108

The reaction steps and conditions for the synthesis of compound 108 andits methanesulfonate from the intermediate 108-1 were the same as thosein the second to fifth steps of example 101, except that theintermediate 101-1 in example 101 was replaced with the intermediate108-1. Data for compound 108: LCMS (parent molecule) C₂₈H₃₂F₃N₈O₃: (ES,m/z): 585.2 [M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm):59.50 (s, 1H), 9.25 (br s, 2H), 8.49 (d, J=6.0 Hz, 1H), 7.74 (d, J=6.0Hz, 1H), 7.42-7.40 (m, 1H), 7.23-7.21 (m, 1H), 7.27-7.22 (m, 1H),7.11-7.02 (m, 2H), 6.78-6.63 (m, 1H), 6.27 (d, J=17.1 Hz, 1H), 5.78 (d,J=10.5 Hz, 1H), 4.85 (s, 2H), 3.85 (s, 3H), 3.50-3.20 (m, 4H), 2.83-2.73(m, 6H), 2.67 (s, 3H), 2.37 (s, 6H).

Example 109

1. Synthesis of Intermediate 109-1

Under a nitrogen atmosphere, the intermediate 048-2 (3.0 g, 12.2 mmol)as a raw material was dissolved in 30 mL of N,N-dimethylformamide in a100 mL three-necked flask at room temperature. The reaction system wascooled to 0° C. and sodium hydride (731 mg, 18.2 mmol) was added theretoin batches. Next, the reaction was cared out at 0° C. for 0.5h, and1,2-difluoro-2-bromoethane (3.48 g, 20.0 mmol) was added into thereaction system, then the reaction was carried out at room temperaturefor 2h. After detecting the reaction was completed, the reaction mixturewas poured into 100 mL of ice water to quench the reaction. Theresulting mixture was extracted with 100 mL of ethyl acetate twice, theorganic phases were combined and washed with 100 mL of saturated brinetwice, dried and concentrated to dryness. The resulting residue waspurified by silica gel column chromatography (eluent, EA:PE=0-20%), andthe product fraction was collected, concentrated to dryness to give 1.23g of the intermediate 109-1 (33%) as a red solid. LCMS: 311.0.

2. Synthesis of Compound 109

The reaction steps and conditions for the synthesis of compound 109 andits methanesulfonate from the intermediate 109-1 were the same as thosein the second to fifth steps of example 101, except that theintermediate 101-1 in example 101 was replaced with the intermediate109-1. Data for compound 109: LCMS (parent molecule) C₂₈H₃₂F₂N₈O₃: (ES,m/z): 567.2 [M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm):δ9.50 (s, 1H), 9.26 (br s, 2H), 8.49-8.47 (d, J=6 Hz, 1H), 8.16-8.11 (m,2H), 7.78-7.76 (d, J=6 Hz, 1H), 7.35-7.33 (m, 1H), 7.24-7.19 (m, 1H),7.11-7.01 (m, 2H), 6.78-6.63 (m, 1H), 6.30-6.24 (m, 1H), 5.80-5.76 (m,1H), 4.85 (s, 2H), 3.85 (s, 3H), 3.50-3.20 (m, 4H), 2.83-2.73 (m, 6H),2.67 (s, 3H), 2.37 (s, 6H).

Example 110

1. Synthesis of Intermediate 110-1

Under a nitrogen atmosphere, 2-nitrofluorobenzene (20 g, 141 mmol) as araw material was dissolved in 500 mL of anhydrous ethanol in a 1000 mLof three-necked flask at room temperature, followed by addingmethylamine hydrochloride (28.5 g, 422 mmol) and 50 mL of water into thereaction system. The reaction was raised to 100° C. and carried outovernight. Next day, after detecting the reaction was completed, thereaction system was cooled to room temperature, concentrated to dryness.The resulting residue was purified by silica gel column chromatography(eluent: PE:EA=5:1). The product was collected, concentrated to drynessto give 18.0 g of the intermediate 110-1 (83%) as a yellow solid. LCMS:153.0.

2. Synthesis of Intermediate 110-2

Under a nitrogen atmosphere, the intermediate 110-1 (15.0 g, 98.6 mmol)as a raw material was dissolved in in 500 mL of methanol in 1000 mLthree-necked flask at room temperature, and palladium on carboncontaining water (5.0 g, 9.86 mmol) and ammonium formate (30.0 g, 476mmol) were sequentially added into the flask, then the reaction wascarried out at room temperature for 2h. After detecting the reaction wascompleted, the reaction system was filtered under suction; the filtratewas collected, concentrated to dryness. 200 mL of water was added intothe residue, and the resulting mixture was extracted with 100 mL ofdichloromethane three times. The organic phases were combined, driedover anhydrous sodium sulfate and concentrated to dryness to give 10.0 gof the intermediate 110-2 (83%) as a yellow solid. LCMS: 123.0.

3. Synthesis of Intermediate 110-3

Under a nitrogen atmosphere, the intermediate 110-2 (10.0 g, 81.9 mmol)as a raw material was dissolved in 500 mL of pyridine in a 1000 mLthree-necked flask at room temperature and sulfonamide (7.8 g, 81.2mmol) was added to the reaction flask. After completion of the reaction,the reaction was heated to 120° C. and carried out for 1 hour. Afterdetecting the reaction was completed, the reaction system was cooled toroom temperature. The reaction mixture was concentrated to dryness. Theresulting residue was purified by silica gel column chromatography(eluent: PE:EA=10: 1-1:1), and then the resulting product was collectedand concentrated to dryness to give 8.5 g of the intermediate 110-3(56%) as a brown solid, LCMS: 185.0.

4. Synthesis of Intermediate 110-4

Under a nitrogen atmosphere, the intermediate 110-3 (3.2 g, 17.4 mmol)as a raw material was dissolved in 200 mL of anhydrous DMF in a 500 mLthree-necked flask at room temperature, and then anhydrous potassiumcarbonate (6.8 g, 49.2 mmol) and 2,4-dichloropyrimidine (2.5 g, 16.8mmol) were added to the reaction flask, then the reaction system washeated to 100° C. and maintained for overnight. Next day, afterdetecting the reaction was completed, the reaction was cooled to roomtemperature and 500 mL of ice water was added to quench the reaction.The reaction mixture was extracted with 200 mL of dichloromethane threetimes. The combined phases were combined, dried over anhydrous sodiumsulfate and concentrated to dryness. The resulting residue was purifiedby silica gel column chromatography (eluent: PE:EA=10:1-1:1). Theproduct was collected, concentrated to dryness to give 1.5 g of theintermediate 110-4 (29%) as a yellow solid. LCMS: 297.0.

5. Synthesis of Compound 110

The reaction steps and conditions for the synthesis of compound 110 andits methanesulfonate from the intermediate 110-4 were the same as thosein the second to fifth steps of example 101, except that theintermediate 110-1 in example 101 was replaced with the intermediate110-4. Data for compound 110: LCMS (parent molecule) C₂₆H₃₂N₈O₄S: (ES,m/z): 553 [M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm):δ9.50 (s, 1H), 9.21 (br s, 1H), 8.99 (s, 1H), 8.46 (d, J=6 Hz, 1H), 8.09(s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.20-7.16 (m, 2H), 7.01-6.89 (m, 3H),6.70-6.60 (m, 1H), 6.28 (d, J=17.1 Hz, 1H), 5.78 (d, J=11.1 Hz, 1H),3.83 (s, 3H), 3.33-3.29 (m, 7H), 2.82 (s, 3H), 2.80 (s, 3H), 2.73 (s,3H), 2.15 (s, 6H).

Example 111

1. Synthesis of Intermediate 111-4

The reaction steps and conditions for the synthesis of the intermediate111-4 from 2-nitrofluorobenzene as a raw material were the same as thosein the first to fourth steps of example 110, except that methylamine inexample 110 was replaced with ethylamine. LCMS for the intermediate111-4: 311.0.

2. Synthesis of Compound 111

The reaction steps and conditions for the synthesis of compound 111 andits methanesulfonate from the intermediate 1114 were the same as thosein the second to fifth steps of example 101, except that theintermediate 101-1 in example 101 was replaced with the intermediate111-4. Data for compound 111: LCMS (parent molecule) C₇H₃₄NO₄S: (ES,m/z): 567 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm): δ9.55 (s, 1H), 9.24(br s, 1H), 9.07 (br s, 1H), 8.45 (d, J=5.7 Hz, 1H), 8.10 (s, 1H),7.89-7.87 (m, 1H), 7.21-7.13 (m, 2H), 7.02-6.86 (m, 3H), 6.71-6.62 (m,1H), 6.28 (d, J=16.5 Hz, 1H), 5.78 (d, J=10.8 Hz, 1H), 3.97-3.90 (m,2H), 3.74 (s, 3H), 3.31-3.20 (m, 4H), 2.82 (s, 3H), 2.81 (s, 3H), 2.70(s, 3H), 2.45 (s, 6H), 1.34-1.23 (m, 3H).

Example 112

1. Synthesis of Intermediate 112-1

Under a nitrogen atmosphere, dimethyl sulfide (11 g, 177 mmol) wasdissolved in 500 mL of methylene chloride in a 1000 mL of four-neckedflask at room temperature. The reaction was cooled to 0° C., andN-chlorosuccinimide (23 g, 172 mmol) was added to the reaction system at0° C. Next, the reaction system was cooled to −20° C. and the indole (20g, 171 mmol) as a raw material was added to the reaction system. Then,the reaction mixture was heated to room temperature and the reaction wascarried out for 1 hour. After the reaction was completed, the reactionmixture was concentrated to dryness and the resulting residue wasdissolved in 200 mL of p-xylene, then the reaction system was heated toreflux for 30 minutes. After completion of the reaction, the reactionsystem was cooled to room temperature. The reaction mixture wasconcentrated to dryness and the residue was purified by silica gelcolumn chromatography (eluent, EA/PE=1:30-1:5). The product wascollected, and concentrated to dryness to give 11.0 g of theintermediate 112-1 (39%) as a yellow solid. LCMS: 163.2.

2. Synthesis of Intermediate 112-2

Under a nitrogen atmosphere, the intermediate 112-1 (10 g, 61.3 mmol) asa raw material was dissolved in 500 mL of dichloromethane in a 1000 mLfour-necked flask, and m-chloroperbenzoic acid (m-CPBA) (26 g, 150.67mmol) was added to the reaction system. Next, the reaction was carriedout at room temperature overnight. After completion of the reaction, thereaction mixture was directly concentrated to dryness and the resultingresidue was purified by silica gel column chromatography (eluent:EA:PE=1:10-1:3). The product was collected and concentrated to drynessto give 3.5 g of the intermediate 112-2 (29%) as a yellow solid. LCMS:195.2.

3. Synthesis of Intermediate 112-3

Under a nitrogen atmosphere, the intermediate 112-2 (3.5 g, 17.9 mmol)as a raw material was dissolved in 150 mL of anhydrous DMF in a 500 mLthree-necked flask at room temperature. The reaction was cooled to 0° C.and sodium hydride (60%) (800 mg, 21 mmol) was added thereto in batches.Next, the reaction was performed for 10 min at 0° C. Next,2,4-dichloropyrimidine (2.6 g, 20.1 mmol) was added into the reactionsystem, after that, the reaction was heated to room temperature andcarried out for 2h. After the reaction was completed, the reactionmixture was poured into 500 mL of ice water to quench the reaction. Theresulting mixture was extracted with 200 mL of ethyl acetate threetimes. The organic phases were combined and washed with 200 mL ofsaturated brine once. The organic phases were dried over anhydroussodium sulfate and concentrated to dryness. The resulting residue waspurified with silica gel column chromatography (EA:PE=1:20-1:5). Theorganic phases were collected and concentrated to dryness to give 1.2 gof the intermediate 112-3 (22%) as a yellow solid. LCMS: 307.8.

4. Synthesis of Compound 112

The reaction steps and conditions for the synthesis of compound 112 andits methanesulfonate from the intermediate 112-3 were the same as thosein the second to fifth steps of example 101, except that theintermediate 101-1 in example 101 was replaced with the intermediate112-3. Data for compound 112: LCMS (parent molecule) C₂₈H₃₃N₇O₄S: (ES,m/z): 564 [M+H]⁺. ¹H-NMR: (300 MHz, DMSO-D₆, ppm): δ9.48 (s, 1H), 9.42(s, 1H), 9.28 (br s, 1H), 8.75 (s, 1H), 8.68 (br s, 1H), 8.38-8.32 (m,2H), 7.88-7.85 (m, 1H), 7.38-7.33 (m, 2H), 7.08 (s, 1H), 6.74-6.25 (m,2H), 6.25 (d, J=17.1 Hz, 1H), 5.76 (d, J=11.1 Hz, 1H), 3.86 (s, 3H),3.33-3.19 (m, 7H), 2.85-2.84 (m, 6H), 2.67 (s, 3H), 2.36 (s, 6H).

Example 113

1. Synthesis of Intermediate 113-1

Under a nitrogen atmosphere, indazole (20 g, 169 mmol) as a raw materialwas dissolved in 500 mL of DMF at 1000 mL of a single-necked flask atroom temperature, followed by sequentially adding iodine (43 g, 169mmol) and potassium hydroxide (38 g, 677 mmol). Next, the reaction wascarried out overnight. After detecting the reaction was completed, thereaction system was quenched with 300 mL of ice water. The resultingmixture was extracted with 300 mL of methylene chloride three times, andthe organic phases were combined, washed with 300 mL of saturated brinethree times and dried over anhydrous sodium sulfate and concentrated todryness. The resulting residue was purified by silica gel columnchromatography (eluent: EA/PE (1:10-1:5)), and the organic phase of theproduct was collected and concentrated to dryness to give 30% of theintermediate 113-1 (73%) as a white solid. LCMS: 244.9

2. Synthesis of Intermediate 113-2

Under a nitrogen atmosphere, the intermediate 113-1 (15 g, 61.5 mmol) asa raw material was dissolved in 500 mL of anhydrous DMF in a 1000 mLthree-necked flask at room temperature. The reaction system was cooledto 0° C. and sodium hydride (2.2 g, 92.2 mmol) was added thereto inbatches for 10 min. Next, the reaction was carried out at 0° C. for 1h,iodoisopropane (15.7 g, 92.4 mmol) was added into therein, followed bythat the reaction was heated to 100° C. and carried out overnight. Afterdetecting the reaction was completed, the reaction system was cooled toroom temperature and quenched with 100 mL of ice water. The resultingmixture was extracted with 500 mL of dichloromethane three times, theorganic phases were combined and washed with 100 mL of saturated brinethree times, dried over anhydrous sodium sulfate and concentrated todryness. The resulting residue was purified by silica gel columnchromatography (eluent: EA:PE (1:10-1:5)), and the organic phases werecollected, concentrated to dryness to give 13 g of the intermediate113-2 (74%) as a yellow solid. LCMS: 287.0.

3. Synthesis of Intermediate 113-3

Under a nitrogen atmosphere, the intermediate 113-2 (3.0 g, 10.5 mmol)as a raw material was dissolved in 100 mL of 1,4-dioxane in 250 mL of athree-necked flask at room temperature, followed by sequentially addinghexamethylditin (4.15 g, 12.7 mmol) andtetrakis(triphenylphosphine)palladium (1.21 g, 1.05 mmol). Next, thereaction system was heated to 105° C. and carried out overnight. Afterdetecting the reaction was completed, the reaction system was cooled toroom temperature and the resulting mixture was used directly in the nextstep reaction.

4. Synthesis of Intermediate 113-4

Under a nitrogen atmosphere, the reaction mixture (the intermediate113-3) (3.40 g, 10.5 mmol) obtained in the previous step was dissolvedin about 100 mL of solution of 1,4-dioxane in a 500 mL three-neckedflask at room temperature, followed by sequentially adding2,4-dichloropyrimidine (1.7 g, 11.4 mmol) andtetrakis(triphenylphsophine)palladium (1.21 g, 1.05 mmol). Next, thereaction system was heated to 105° C. overnight. After detecting thereaction was completed, the reaction system was cooled to roomtemperature and the reaction mixture was quenched with 200 mL of icewater. The resulting mixture was extracted with 200 mL ofdichloromethane twice, then the organic phases were combined, washedwith 400 mL of saturated brine three times, dried over anhydrous sodiumsulfate, and concentrated to dryness. The resulting residue was purifiedby silica gel column chromatography (eluent: EA/PE (1: 10-1:3)). Theorganic phases were collected and concentrated to dryness to give 1.9 gof the intermediate 113-4 (66%) as a white solid. LCMS: 273.1.

5. Synthesis of Compound 113

The reaction steps and conditions for the synthesis of compound 113 andits methanesulfonate from the intermediate 113-4 were the same as thosein the second to fifth steps of example 101, except that theintermediate 101-1 in example 101 was replaced with the intermediate113-4. Data for compound 113: LCMS (parent molecule) C₂₉H₃₆N₈O₂: (ES,m/z): 529.3[M+H]⁺. ¹H-NMR (methanesulfonate): (300 MHz, DMSO-D₆, ppm): δ9.59 (s, 1H), 9.26 (br s, 2H), 8.45 (d, J=5.7 Hz, 1H), 8.37 (br s, 1H),8.30 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.57 (d, J=5.7 Hz, 1H), 7.48-7.43(m, 1H), 7.24-7.19 (m, 1H), 7.06 (s, 1H), 6.72-6.64 (m, 1H), 6.28 (d,J=16.2 Hz, 1H), 5.78 (d, J=11.1 Hz, 1H), 5.20-5.11 (m, 1H), 3.87 (s,3H), 3.32-3.45 (m, 4H), 2.84 (s, 3H), 2.83 (s, 3H), 2.67 (s, 3H), 2.36(s, 6H), 1.58 (s, 3H), 1.55 (s, 3H).

Experimental Example 1

Experiment of Cell Growth Inhibition

The compounds that were preferentially targeted for EGFR targetingcertain mutations and relatively weak in wild-type EGFR were identifiedby determining the growth of cells. The NCI-H1975 cell line is a humannon-small cell lung cancer cell containing T790M and L858R EGFRmutations, and the cell is grown in RPMI-1640 medium (GIBCO) containing10% fetal bovine serum (FBS). The LoVo cell line is a wild-type EGFRhuman colon adenocarcinoma cell, and is grown in F-12K medium (GIBCO)containing 10% FBS. NCI-H2073 cell line is a wild-type EGFR humannon-small cell lung cancer cell and grown in ACL-4 medium containing 10%FBS. The growth rate of NCI-H1975, LoVo and NCI-H₂₀₇₃ cells was detectedby Cell Titer-Glo luminescence activity assay (Promega # G7572).

Briefly, trypsin was used for digesting cells in the logarithmic growthphase. 96-well plates were seeded with 50,000 Lovo or NCI-H2073 cells,2500-3000 NCI-H1975 cells per well and provided with blank control wellscontaining only nutrient solution without inoculated cell, and theplates were incubated in a humidified incubator with 5% CO₂ at 37° C.After 24 hours, the DMSO solution of the different compounds was dilutedwith a cell culture medium at 3.16 times per time to eight differentconcentrations from high to low levels. The concentration of test drugin NCI-H1975 cells was from 0.03 nM to 100 nM, and that in LoVo andNCI-H2073 cells was from 3 nM to 10 μM. The cell culture mediumcontaining the different compounds was then added to a 96-well cellplate in which one cell control well comprising cell culture medium onlycontaining DMSO was provided. After a drug treatment for 72 hours, thecell plates were removed from the incubator and allowed to stand at roomtemperature for 30 minutes. Next, Cell Titer-Glo reagent was added tothe wells and the 96-well cell plate was shaken at room temperature for10 minutes to induce cell lysis. The 96-well cell plate was placed onthe bench for 2 minutes to stabilize the luminescence signal. Finally,the 96-well cell plate was placed in an EnVision Multi-labeledMicroplate Reader (PerkinElmer), and the signal was read with anintegral time of 0.5 seconds.

Percentage of cell growth inhibition %=(maximum signal−compoundsignal)/(maximum signal−minimum signal)*100%  Formula:

The maximal signal was obtained from the cell control well which weretreated with the DMSO solution having no any compound;

The compound signal was obtained from the drug-treated cell wells towhich the compound was added;

The minimum signal was obtained from a blank control well to which nocells and only nutrient solution was added.

The cell growth inhibition curve was calculated by GraphPad Prism V5.0software and the compound concentration required to give a 50%inhibition was calculated based on this data, i.e., IC₅₀ of compounds.

The results are listed in Table 1 below.

TABLE 1 Results of compound activity Compound # NCI-H1975 Lovo IC₅₀NCI-H2073 or its salt # IC₅₀ (nM) (nM) IC₅₀ (nM)   1. (HCl)_(n) 5.4 2257230   2. (MsOH)₃ 6.1 2297 474   3. (MsOH)₂ 6.2 3086 295   4. (MsOH)₃ 8.62573 500   5. (MsOH)₃ 5.4 4230 335   6. (HCl)_(n) >100 4978   7. (MsOH)₃9.9 2168 760   8. MsOH 113 1937 870   9. (MsOH)₂ 13.0 2065 1130  10.(MsOH)₃ >100 3019  11. (MsOH)₂ 35.4 1272  12. (MsOH)₂ 35.2 1718  13.(MsOH)₂ >100 444  14. (MsOH)₂ >100 481  15. (MsOH)₂ >100 333  16.(MsOH)₂ 82.2 569  17. (MsOH)₂ 100 >10000  18. (MsOH)₃ 43.6 520  19. MsOH48.5 955  20. (MsOH)₄ >100 954  21. (MsOH)₂ >100 >10,000  22.20.5 >10000 >10000  23. 90.8 2284  24. (MsOH)₃ >100 2579  25.(MsOH)₂ >100 5247  26. (MsOH)₂ >100 5128  27. (MsOH)₃ 84.0 1812 28. >100 538  29. (MsOH)₂ 13.0 2519 2520  30. (MsOH)₂ >100 2551  31.(MsOH)₃ >100 846  32. (MsOH) >100 >10000  33. HCl >100 1432  34. (MsOH)₃39.9 446  35. (MsOH)₃ 48.4 912  36. (MsOH)₃ 15.0 4328 410  37. (MsOH)₃8.1 4658 260  38. (HCl)_(n) 8.2 2990 476  39. (MsOH)₃ 0.8 3388 18  40.(MsOH)₃ 1.3 6093 183  41. (HCl)_(n) 7.4 >10000 340  42. (HCl)_(n) 7.17095 490  43. (HCl)_(n) 18.1 2171  44. (HCl)_(n) 14.0 870 280  45.(HCl)_(n) >100 1090  46. (MsOH)₂ 155 1166  47. (MsOH)₂ 134 1625  48.(HCl)_(n) 5.5 2344 435  49. (HCl)_(n) 0.7 2263 135  50. (HCl)_(n)9.2 >10000 290  51. (HCl)_(n) 2.6 1276 325  52. (HCl)_(n) 5.2 6103 220 53. (HCl)_(n) 14.0 2860 690  54. (HCl)_(n) 38.2 738  55. (HCl)_(n) 1003227  56. (HCl)_(n) 36.0 4180 >10000  57. (HCl)_(n) 8.2 280  58.(HCl)_(n) 1.6 116  59. (HCl)_(n) 1.3 4180 120  60. (HCl)_(n) 1.4 4070110  61. (HCl)_(n) 1.5 29  62. (HCl)_(n) 3.2 270  63. (HCl)_(n) 4.8 410 64. (HCl)_(n) 6.0 310  65. (MsOH)₂ 1.9 151  66. (MsOH)₃ 3.6 201  67.81.7 4098  68. (MsOH)₂ 0.4 43  69. (MsOH)₃ 0.8 63  70. (MsOH)₂ 0.5 46 71. (MsOH)₂ 0.4 64  72. (MsOH)₃ 2.7 282  73. (MsOH)₂ 1.7 179  74.(MsOH)₃ 14.4 463  76. (MsOH)₂ 1.0 56 101. (MsOH)₂ 5.5 193 102. (MsOH)₂6.4 170 103. (MsOH)₂ 13.1 300 104. (MsOH)₂ 16.5 977 105. (MsOH)₂ 15.7543 106. (MsOH)₂ 4.7 155 107. (MsOH)₂ 7.4 185 108. (MsOH)₂ 5.9 253 109.(MsOH)₂ 4.5 268 110. (MsOH)₂ 2.9 103 111. (MsOH)₂ 2.7 49 112. (MsOH)₂100 5425 113. (MsOH)₂ 26.5 595

Experimental Example 2

Comparison of the concentration of the metabolite AZ5104 in rats' bodyplasma of the pyrimidine compounds according to the present inventionand AZD9291

Briefly, AZD9291 or the compound 49.(HCl)_(n) of Example 49 or thecompound 104.(MsOH)₂ of Example 104 were administered intragastricallyto 200-220 g of adult male rats at amount of 10 mg/kg. Eachadministration group had two to three rats. After administration, 150 μlof blood was extracted from the vein on the rat tail at different times(0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours), put in a tube with K2EDTAand placed immediately on ice. Then, the blood sample was centrifuged incentrifuge with a 4-degree at a speed of 2000 g for 15 minutes. Theplasma was separated and placed in a small tube and stored in arefrigerator at −80° C. The concentration of parent drug and metabolitein plasma sample was analyzed by LC/MS.

The results are listed in Table 2 below.

TABLE 2 Comparison of the concentration of parent drug and metaboliteAZ5104 in plasma sample of rats' body Compound # Parent drug AUC AZ5104AUC or its salt # (hr* uM) (hr* uM) AZD9291 0.64 0.02 49. (HCl)_(n) 0.91lower than the limit of quantification (BQL) 104. (MsOH)₂ 1.49 lowerthan the limit of quantification (BQL)

1. A pyrimidine compound represented by the following formula (I) or apharmaceutically acceptable salt, stereoisomer, prodrug molecule orsolvate thereof:

wherein, R¹ is hydrogen, deuterium, halogen or cyano; R² is a C1-C6alkyl, CD₃, or halogen-substituted C1-C6 alkyl; X is NR³ or o; Y isNHC(═O) or NHS(═O)₂, and the nitrogen in the NHC(═O) or NHS(═O)₂ isbonded to the benzene ring in formula (I); R³ is a C1-C6 alkyl, C1-C6alkoxy, CD₃, C1-C6 alkoxy C1-C6 alkyl; R⁴ is a C1-C3 alkyl,unsubstituted or substituted with 1-3 substituents, wherein saidsubstituent is a C1-C3 alkyl, CD₃, C1-C3 alkoxy, methanesulfonyl, NR⁷R⁸or a 3- to 6-membered heterocyclic group containing 1 to 2 heteroatomsselected from N and O, unsubstituted or substituted with hydroxy orC1-C3 alkyl; or, R³ and R⁴, together with the nitrogen atom to whichthey are bonded, form a 4-6 membered heterocyclic ring containing 1 to 4nitrogen or oxygen and having one or more substituents, and thesubstituent is amino, dimethylamino, C1-C3 alkoxy, or a 4- to 6-memberedheterocyclic group containing 1 to 2 heteroatoms selected from N and O,unsubstituted or substituted with C1-C3 alkyl; R⁵ is a fused ring formedby two rings, and the fused ring formed by two rings is optionallysubstituted with 1-3 substituents, wherein the two rings forming thefused ring are each independently benzene, a 5-7-membered heterocyclicring or a 5-7-membered heteroaromatic ring, wherein the 5-7 memberedheterocyclic or 5-7 membered heteroaromatic ring contains 1-4heteroatoms selected from S, N or O, and the substituent is oxo group(═O) or R⁶, R⁶ is hydrogen, C1-C3 alkyl, CD₃, C1-C3 alkylsulfonyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heteroaryl, orhalogen-substituted C1-C3 alkyl, wherein the 4-6 membered heterocyclylor 4-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N,O and S and is optionally substituted with C1-C2 alkyl; R⁷ and R⁸ areeach independently C1-C3 alkyl, CD₃, C1-C3 alkoxy or C3-C5 cycloalkyl;and when R¹ is hydrogen, R² is methyl, X is NCH₃, Y is NHC(═O), R⁴ isdimethylaminoethyl, R⁵ cannot be

when R¹ is hydrogen, R² is methyl, X is NR³, Y is NHC(═O), R³ is methyl,R⁴ is dimethylaminoethyl, R⁵ is

R⁶ is methyl, no hydrogen in any one of R¹, R², R³, R⁴ and R⁶ can besubstituted by deuterium.
 2. The pyrimidine compound, orpharmaceutically acceptable salt, stereoisomer, prodrug molecule orsolvate thereof according to claim 1, wherein R¹ is hydrogen, deuterium,fluorine, chlorine or cyano; R² is a C1-C3 alkyl, CD₃, or C1-C3 alkylsubstituted with 1 to 3 fluorines or chlorines; X is NR³ or O; R³ is aC1-C3 alkyl, CD₃, or C1-C3 alkoxyC1-C3alkyl; Y is NHC(═O) or NHS(═O)₂;R⁴ is selected from the following groups:

or, when X is NR³, R³ and R⁴, together with the nitrogen atom to whichthey are bonded, form a nitrogen-containing heterocyclic ring withsubstituent(s), and the nitrogen-containing heterocyclic ring withsubstituent(s) is selected from the following heterocyclic groups

R⁵ is group selected from the following groups:

R⁶ is hydrogen, methyl, CD₃, ethyl, isopropyl, methylsulfonyl, C3-C6cycloalkyl, or fluorine-substituted C1-C3 alkyl; and when R¹ ishydrogen, R² is methyl, X is NCH₃, Y is NHC(═O), R⁴ isdimethylaminoethyl, R⁵ cannot be

when R¹ is hydrogen, R² is methyl, X is NR₃, Y is NHC(═O), R³ is methyl,R⁴ is dimethylaminoethyl, R⁵ is

R⁶ is methyl, no hydrogen in any one of R¹, R², R³, R⁴ and R⁶ can besubstituted by deuterium.
 3. The pyrimidine compound or pharmaceuticallyacceptable salt, stereoisomer, prodrug molecule or solvate thereofaccording to claim 1, wherein R¹ is hydrogen, R² is methyl or CD₃, X isNR³, R³ is CH₃, CD₃, ethyl or methoxyethyl, Y is NHC(═O) or NHS(═O)₂, R⁴is dimethylaminoethyl, R⁵ is selected from the following groups:

wherein, R⁶ is hydrogen, methyl, CD₃, ethyl, isopropyl, methylsulfonyl,C3-C6 cycloalkyl, or fluorine-substituted C1-C3 alkyl.
 4. A pyrimidinecompound represented by the following formula (I), or a pharmaceuticallyacceptable salt, stereoisomer, prodrug molecule or solvate thereof:

wherein, R¹ is hydrogen, deuterium, halogen or cyano; R² is a C1-C6alkyl, CD₃, or halogen-substituted C1-C6 alkyl; X is NR₃ or O; Y isNHC(═O) or NHS(═O)₂, and the nitrogen in the NHC(═O) or NHS(═O)₂ isbonded to the benzene ring in formula (I); R³ is a C1-C6 alkyl, C1-C6alkoxy, CD₃, C1-C6 alkoxy C1-C6 alkyl; R⁴ is a C1-C3 alkyl unsubstitutedor substituted with 1-3 substituents, wherein said substituent is aC1-C3 alkyl, CD₃, C1-C3 alkoxy, methanesulfonyl, NR⁷R⁸ or a 3- to6-membered heterocyclic group containing 1 to 2 heteroatoms selectedfrom N and O unsubstituted or substituted with hydroxyl or C1-C3 alkyl;or, R³ and R⁴, together with the nitrogen atom to which they are bonded,form a 4-6 membered heterocyclic ring containing 1 to 4 nitrogen oroxygen and having one or more substituents, and the substituent isamino, dimethylamino, C1-C3 alkoxy, or a 4- to 6-membered heterocyclicgroup containing 1 to 2 heteroatoms selected from N and O unsubstitutedor substituted with C1-C3 alkyl; R⁵ is a fused ring formed by two rings,and the fused ring formed by two rings is optionally substituted with1-3 substituents, wherein the two rings forming the fused ring are eachindependently benzene, a 5-7-membered heterocyclic ring or a5-7-membered heteroaromatic ring, wherein the 5-7 membered heterocyclicor 5-7 membered heteroaromatic ring contains 1-4 heteroatoms selectedfrom S, N or O, and the substituent is oxo group (═O) or R, R⁶ ishydrogen, C1-C3 alkyl, CD₃, C1-C3 alkylsulfonyl; R⁷ and R⁸ are eachindependently C1-C3 alkyl, CD₃, C1-C3 alkoxy or C3-C5 cycloalkyl; andwhen R¹ is hydrogen, R² is methyl, X is NCH₃, Y is NHC(═O), R⁴ isdimethylaminoethyl, R⁵ cannot be

when R¹ is hydrogen, R² is methyl, X is NR₃, Y is NHC(═O), R³ is methyl,R⁴ is dimethylaminoethyl, R⁵ is

R⁶ is methyl, no hydrogen in any one of R¹, R², R³, R⁴ and R⁶ can besubstituted by deuterium.
 5. The pyrimidine compound, orpharmaceutically acceptable salt, stereoisomer, prodrug molecule orsolvate thereof according to claim 4, wherein R¹ is hydrogen, deuterium,fluorine, chlorine or cyano; R² is a C1-C3 alkyl, CD₃, or C1-C3 alkylsubstituted with 1 to 3 fluorines or chlorines; X is NR³ or O; R³ is aC1-C3 alkyl, CD₃, or C1-C3 alkoxyC1-C3alkyl; Y is NHC(═O) or NHS(═O)₂;R⁴ is selected from the following groups:

or, when X is NR³, R³ and R⁴, together with the nitrogen atom to whichthey are bonded, form a nitrogen-containing heterocyclic ring withsubstituent(s), and the nitrogen-containing heterocyclic ring withsubstituent(s) is selected from the following heterocyclic groups:

R⁵ is a group selected from the following groups:

R⁶ is hydrogen, methyl, CD₃, ethyl, isopropyl, or methylsulfonyl; andwhen R¹ is hydrogen, R² is methyl, X is NCH₃, Y is NHC(═O), R⁴ isdimethylaminoethyl, R⁵ cannot be

when R¹ is hydrogen, R² is methyl, X is NR³, Y is NHC(═), R³ is methyl,R⁴ is dimethylaminoethyl, R⁵ is

R⁶ is methyl, no hydrogen in any one of R¹, R², R³, R⁴ and R⁶ can besubstituted by deuterium.
 6. The pyrimidine compound or pharmaceuticallyacceptable salt, stereoisomer, prodrug molecule or solvate thereofaccording to claim 4, wherein R¹ is hydrogen, R² is methyl or CD₃, X isNR³, R³ is CH₃, CD₃, ethyl or methoxyethyl, Y is NHC(═O) or NHS(═O)₂, R⁴is dimethylaminoethyl, R⁵ is selected from the following groups:

wherein, R⁶ is hydrogen, methyl, CD₃ ethyl, isopropyl or methylsulfonyl.7. The pyrimidine compound or pharmaceutically acceptable salt,stereoisomer, prodrug molecule or solvate thereof according to claim 4,wherein R¹ is hydrogen, R² is methyl or CD₃, X is NR³, R³ is CH₃, CD₃,ethyl or methoxyethyl, Y is NHC(═O) or NHS(═O)₂, R⁴ isdimethylaminoethyl, R⁵ is selected from the following groups:


8. The pyrimidine compound or pharmaceutically acceptable salt,stereoisomer, prodrug molecule or solvate thereof according to claim 4,wherein R¹ is hydrogen, R² is methyl or CD₃, X is NR³, R³ is CD₃ orethyl, Y is NHC(═O) or NHS(═O)₂, R⁴ is selected from the followinggroups:

R⁵ is selected from the following groups:

wherein R⁶ is selected from hydrogen, methyl, CD₃, ethyl, isopropyl, ormethylsulfonyl.
 9. The pyrimidine compound or pharmaceuticallyacceptable salt, stereoisomer, prodrug molecule or solvate thereofaccording to claim 4, wherein R¹ is hydrogen, R² is methyl or CD₃, X isNR³, R³ is CD₃ or ethyl, Y is NHC(═O) or NHS(═O)₂, R⁴ is selected fromthe following groups:

R⁵ is selected from the following groups:


10. A pyrimidine or pyridine compound, or a pharmaceutically acceptablesalt, stereoisomer, prodrug molecule or solvate thereof, wherein thepyrimidine or pyridine compound is the following compound:


11. A pharmaceutical composition, comprising a therapeutically effectiveamount of one or more of the compound, pharmaceutically acceptable saltthereof, stereoisomer, prodrug molecule and/or solvate thereof accordingto any one of claims 1 to 10, and one or more pharmaceutical excipients.12. An use of the compound, pharmaceutically acceptable salt thereof,stereoisomer, prodrug molecule and/or solvate thereof according to anyone of claims 1 to 10, in the preparation of a medicament for treatingor preventing a disorder or disease mediated by EGFR in the form of anactivated or resistant mutant, preferably, the disorder or diseasemediated by the EGFR in the form of an activated or resistant mutant isovarian cancer, cervical cancer, colorectal cancer, breast cancer,pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer,leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer,hepatocellular carcinoma, gastrointestinal stromal tumor, thyroidcancer, cholangiocarcinoma, endometrial cancer, kidney cancer,anaplastic large cell lymphoma, acute myeloid leukemia, multiple myelomaor mesothelioma.